Carbidopa prodrugs and derivatives, and compositions and uses thereof

ABSTRACT

Prodrugs of carbidopa, derivatives of carbidopa prodrugs, methods of making prodrugs of carbidopa and derivatives thereof, methods of using prodrugs of carbidopa and derivatives thereof, and compositions of prodrugs of carbidopa and derivatives thereof are disclosed.

[0001] This application claims priority benefit of U.S. ProvisionalApplication No. 60/431,304 filed Dec. 6, 2002.

[0002] Embodiments of the present invention are directed to prodrugs ofcarbidopa and derivatives of carbidopa prodrugs, methods of makingprodrugs of carbidopa and derivatives of carbidopa prodrugs, methods ofusing prodrugs of carbidopa and derivatives of carbidopa prodrugs, andcompositions of prodrugs of carbidopa and derivatives of carbidopaprodrugs.

[0003] Parkinson's disease is a disabling, progressive illness thataffects one in 1,000 people and generally occurs in people over the ageof 50 years. Patients with Parkinson's disease have a deficiency of theneurotransmitter dopamine in the brain as a result of the nigrostriatalpathway disruption caused by degeneration of the substantia nigra.Levodopa (L-dopa or L-3,4-dihydroxyphenylalanine), an immediateprecursor of dopamine, is the most commonly prescribed drug fortreatment of this disease.

[0004] Following oral administration, levodopa is rapidly absorbed viaan amino acid transporter present in the upper small intestine. Due tothe narrow distribution of this transporter system, the window availablefor levodopa absorption is limited and the extent of absorption can bedependent on the rate at which the drug passes through the uppergastrointestinal tract. Approximately 30-50% of the administered dosereaches the systemic circulation after oral administration. The absolutebioavailability of levodopa is dose-dependent, due to saturation of theactive transport pathway (Cheng et al., 1976, Xenobiotica, 6:237-248).Plasma levels of levodopa must be carefully titrated for each patient toachieve the optimal therapeutic activity. If the concentration oflevodopa is too low in plasma (and consequently in the brain) thepatient can experience a return of the symptoms of Parkinson's disease(rigidity, tremor, bradykinesia). On the other hand, motor fluctuationcan become a significant side effect if plasma drug levels are too high.Uncontrolled fluctuations in plasma levodopa levels can greatlycontribute to the incidence of “on-off” fluctuations (diskinesias). Themost effective control of Parkinsonism is observed when plasma levels oflevodopa are maintained in a narrow range, for example, by continuousintraduodenal infusion (Kurlan et al., 1988, Ann. Neurol., 23:589-595).

[0005] Once absorbed, levodopa is rapidly converted to dopamine byL-aromatic amino acid decarboxylase (AADC) in the intestines and liver.It has been known that intestinal metabolism of levodopa is the majorsource of first pass loss of the drug. Intraportal and intravenousadministration gave similar levodopa systemic exposures in rats (Iwamotoet al., 1987, J. Pharm. Pharmacol., 39:421-5). In patients, only 1% ofthe administered dose reaches the central nervous system intact,following transport across the blood-brain barrier by the neutral aminoacid transporter. For this reason, levodopa is normally co-administeredwith a drug designed to inhibit its peripheral decarboxylation (e.g.carbidopa or benserazide). When administered with carbidopa, intactlevodopa is transported into the central nervous system where it can beconverted to dopamine. Carbidopa itself does not cross the blood-brainbarrier to a significant extent, and therefore does not inhibit therequired conversion of levodopa to dopamine in the brain.

[0006] The oral bioavailability of levodopa from conventionalformulations of levodopa/carbidopa (e.g., Sinemet) is 84-99%(Physician's Desk Reference; Yeh et al., 1989, Neurology, 39:25-38). Thehalf-life of levodopa in the plasma of patients is about 50 min whenadministered alone, or 1 to 2 hrs when given with carbidopa. For thisreason, the drug must be administered three or more times per day.

[0007] A formulation of levodopa/carbidopa (Sinemet® CR) intended toprovide a controlled release of both drugs is commercially available.Sinemet® CR is designed for release of both levodopa and carbidopa overa 4-6 hour period. However, absorption of levodopa is limited to thesmall intestine and the resulting bioavailability of levodopa fromSinemet® CR is reduced relative to the immediate release product. Inmost cases, Sinemet® CR must also be given more than twice per day toachieve a therapeutic level of levodopa. Conventional delayed andextended release formulations that target the large intestine areineffective for the sustained delivery of levodopa. A simple entericcoated formulation of levodopa led to increased gastrointestinal sideeffects (nausea) but did not improve absorption (Sandler et al., 1974,Lancet, 16:238-240). A sustained release formulation oflevodopa/carbidopa has been described that employs a swellable matrix(Geomatrix) delivery system to retain the drug in the stomach (GentaJago product licensing information, June 1997). However, thisformulation was designed to be bioequivalent to the commerciallyavailable Sinemet® CR formulation and therefore has not proven capableof providing the desired goal of a once or twice per day regimen.

[0008] The potential use of various simple esters as prodrugs oflevodopa as a means to improve the pharmacokinetics of the drug has beenproposed (U.S. Pat. Nos. 5,017,607; 4,826,875; 4,873,263; 4,663,349;4,771,073; 4,311,706; Juncos et al., 1987, Neurology 37:1242; and Cooperet al., 1987, J. Pharm. Pharmacol. 39:809). An oral formulation oflevodopa methyl ester (Levomet®, CHF 1301) has been described (ChiesiPharmaceuticals). The ethyl ester of levodopa (TV-1203) is underclinical investigation as a potential therapy for Parkinsonism whenco-administered with carbidopa (U.S. Pat. No. 5,607,969). A sustainedcellulose formulation of levodopa ethyl ester in a mixture ofhydroxypropylmethyl cellulose, hydroxypropyl cellulose, and acarboxyvinyl polymer has been described (U.S. Pat. No. 5,840,756).However, oral administration of this formulation to healthy adultspretreated with carbidopa produced a plasma levodopa terminal half-lifeof only 2 hr, comparable to that of Sinemet® CR. This result indicatesthat the ester was absorbed faster than the rate of its hydrolysis tolevodopa.

[0009] A pivaloyl ester of levodopa (NB-355) has been described(European Patent No. 0309827). Conversion of the prodrug to levodopa inrat plasma following absorption from an intestinal loop was slow andsustained levels of prodrug were observed, while levels of levodopa werelow. The potential for using ester prodrugs of levodopa to enhancerectal absorption of the drug has been described (U.S. Pat. Nos.4,663,349; 4,771,073; 4,873,263). Notably, the absorption of simplealkyl esters of levodopa has been shown to be greater following rectalabsorption than following oral dosing (et al., Pharm. Res. 1989,6:501-5; et al., Pharm. Res. 1990, 4:384-7). This effect is due to thedecreased abundance of esterases in the large intestine relative to thesmall intestine. Therefore, selective delivery of a prodrug of levodopato the large intestine in a sustained release formulation might beexpected to provide a greater oral bioavailability and a prolongedexposure to the drug.

[0010] The half-life of levodopa is prolonged and its bioavailabilityincreased by the co-administration of carbidopa. Both drugs haverelatively short half-lives (≦2 hr) (Yeh et al., 1989, Neurology,39:25-38). Any method of sustained delivery of levodopa to the systemiccirculation would therefore require a sufficient level of carbidopa tocontinuously inhibit peripheral decarboxylation of levodopa. In order toavoid the need for frequent (more than twice per day) dosing ofcarbidopa, it is necessary to deliver both levodopa and carbidopa (orprodrug thereof) in a sustained manner. It has been proposed that rectalco-administration of an AADC inhibitor such as carbidopa with an esterprodrug of levodopa would be possible as a means to decrease metabolicclearance of levodopa (U.S. Pat. Nos. 4,663,349; 4,771,073; 4,873,263).However, studies in rats have since indicated that absorption ofcarbidopa following rectal administration is poor (Leppert et al., 1988,Pharm. Res., 5:587-591). For this reason, a conventional sustainedrelease formulation of carbidopa is unlikely to achieve the desiredresult of sustained systemic exposure.

[0011] The following publications, patents and patent applications arecited in this application as superscript numbers:

[0012]¹Cheng, et al., Xenobiotica, 1976, 6:237-248.

[0013]²Contin, et al., Clin. Pharmakinet., 1996,30:463-481.

[0014]³Cooper, et al., J. Pharm. Pharmacol. 1987, 39:809.

[0015]⁴Genta Jago product licensing information, June 1997.

[0016]⁵ Greene et al., Protective Groups in Organic Synthesis, ThirdEdition, John Wiley & Sons, 1999, and references cited therein.

[0017]⁶Fix, et al., Pharm. Res., 1989, 6:501-5.

[0018]⁷Fix, et al., Pharm. Res., 1990, 4:384-7.

[0019]⁸Iwamoto, et al., J. Pharm. Pharmacol., 1987, 39:421-5.

[0020]⁹Juncos, et al., Neurology 1987, 37:1742.

[0021]¹⁰Kurlan, et al., Ann. Neurol., 1988, 23:589-59.

[0022]¹¹Larock, Comprehensive Organic Transformations, John Wiley &Sons, Second Edition, 1999.

[0023]¹²Leppert, et al., Pharm. Res., 1988, 5:587-591.

[0024]¹³March, Advanced Organic Chemistry, John Wiley & Sons, FourthEdition, 1992.

[0025]¹⁴Physician's Desk Reference.

[0026]¹⁵Sandler, et al., Lancet, 1974, 16:238-240.

[0027]¹⁶Smith, Organic Synthesis, John Wiley & Sons, 1994.

[0028]¹⁷Yeh, et al., Neurology, 1989, 39:25-38.

[0029]¹⁸“Novel dopa/dopamine prodrugs”, U.S. Pat. No. 4,311,706, Jan.19, 1982.

[0030]¹⁹“Rectally absorbable form of L-dopa”, U.S. Pat. No. 4,663, 349,May 5, 1987

[0031]²⁰“Rectally absorbable form of L-dopa”, U.S. Pat. No. 4,771,073,Sep. 13, 1988

[0032]²¹“Pharmaceutical compositions containing levodopa methyl ester,preparation and therapeutic applications thereof”, U.S. Pat. No.4,826,875, May 2, 1989.

[0033]²²“Rectally absorbable form of L-dopa”, U.S. Pat. No. 4,873,263,Oct. 10, 1989.

[0034]²³“L-dopa derivatives of their acid addition salts, process forproducing same and their use”, U.S. Pat. No. 4,966,915, Oct. 30, 1990.

[0035]²⁴“Method to treat Parkinson's disease”, U.S. Pat. No. 5,017,607,May 21, 1991.

[0036]²⁵“Modified bile acid conjugates, and their use aspharmaceuticals”, U.S. Pat. No. 5,462,933, Oct. 31, 1995.

[0037]²⁶“L-dopa ethyl ester to treat Parkinson's disease”, U.S. Pat. No.5,607,969, Mar. 4, 1997.

[0038]²⁷“Pharmaceutical composition of L-DOPA ester”, U.S. Pat. No.5,840,756, Nov. 24, 1998.

[0039]²⁸“Means to achieve sustained release of synergistic drugs byconjugation”, U.S. Pat. No. 6,051,576, Apr. 18, 2000.

[0040]²⁹“Codrugs as a method of controlled drug delivery”, InternationalPublication No. WO 95/20567, Aug. 8, 1995.

[0041]³⁰U.S. Provisional Application No. 60\023,758 (Attorney DocketNumber 033053 005) filed on Oct. 6, 2000.

[0042]³¹“L-Dopa Derivatives or Their Acid Addition Salts, Process forProducing Same and Their Use,” European Patent No. 0 309 827, Apr. 5,1989.

[0043]³²“Bile acid prodrugs of L-dopa and their use in the sustainedtreatment of Parkinsonism,” International Publication No. WO 02/28882,Apr. 11, 2002.

[0044] All of the above publications, patents and patent applicationsare herein incorporated by reference in their entirety to the sameextent as if each individual publication, patent or patent applicationwas specifically and individually indicated to be incorporated byreference in its entirety.

[0045] Certain embodiments of the present invention are related toprodrugs of carbidopa and derivatives of carbidopa prodrugs, which arecapable of undergoing absorption across the intestinal epithelium viaactive and/or passive transport. In certain embodiments, carbidopaprodrugs and derivatives thereof are capable of absorption over asignificant length of the gastrointestinal tract, including the largeintestine (i.e., colon). Such prodrugs can be incorporated intoconventional sustained release formulations (including osmotic deliverydevices) to provide sustained systemic exposure to carbidopa upon oraladministration to a mammal. Many of such prodrugs and derivatives can becoadministered with levodopa, or a prodrug of levodopa, and in someembodiments also formulated as sustained release compositions, with thelevodopa/carbidopa prodrug compositions together providing prolongedexposure to levodopa at levels necessary to affect sustainedanti-Parkinson's therapy. Certain embodiments include carbidopa prodrugsthat can block first-pass levodopa decarboxylation within the intestinalenterocytes (either as the intact prodrugs themselves, or throughgeneration of carbidopa from prodrug cleavage within the enterocytes)and which can be readily cleaved to provide carbidopa in the systemiccirculation. Levodopa-carbidopa prodrug or derivative thereof orlevodopa prodrug-carbidopa prodrug or derivative thereof sustainedrelease compositions can also be administered together with inhibitorsof catechol O-methyltransferase (COMT) (e.g., entacapone or tolcapone)to further block peripheral clearance of levodopa.

[0046] Among carbidopa prodrugs and derivatives thereof contemplated bycertain embodiments are prodrugs and derivatives in which the terminalamino group of these drugs is blocked with an acyl or alkoxycarbonylgroup. These functionalities undergo cleavage in vivo to liberate theparent drug. Optionally, the carboxyl and/or catechol moieties ofcarbidopa can additionally be masked with promoieties, these promoietiesbeing cleaved either before or after cleavage of the N-terminalpromoiety. Similarly, carboxyl esters and amides derived from carbidopa,which can be cleaved in vivo to release the parent drug, arecontemplated as another class of prodrugs in certain embodiments. Asbefore, the catechol moieties of such prodrugs and derivatives can alsooptionally be masked with promoieties, these promoieties being cleavedeither before or after cleavage of the carboxy-terminal promoiety.Further contemplated by certain embodiments are carbidopa prodrugs andderivatives thereof that can initially undergo cleavage in vivo toliberate dipeptide or dipeptide analogs containing carbidopa. Thesedipeptides can provide the parent drug upon further proteolysis in vivo.Moreover, such prodrugs and derivatives can serve as substrates forpeptide transporters localized in the intestines.

[0047] Suitable catechol protecting moieties in the aforementionedprodrugs can be elaborated by functionalizing one or more of thephenolic hydroxy groups via acylation or other appropriate methods. Thecorresponding esters, carbonates, and (hemi)acetals/(hemi)ketals can becleaved in vivo to regenerate the catechol moieties of the parent drug.

[0048] One aspect provides carbidopa prodrugs and derivatives thereof ofstructural Formula (I):

[0049] a stereoisomer thereof, an enantiomer thereof, a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing, wherein:

[0050] X is selected from —OR¹⁰ and moieties of Formulae (II) and (III):

[0051] where:

[0052] r is an integer from 1 to 6;

[0053] Q is O or —NR¹⁵;

[0054] R¹ is selected from hydrogen and the structure of Formula (IX):

[0055] R⁴ and R⁵ are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroalkyl, substitutedheteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,—C(O)OR²⁷, —C(O)R²⁷, —(CR¹⁶R¹⁷)OC(O)R¹¹, and moieties of Formulae (XVII)and (XVIII):

[0056] wherein o is 1-3, and the cycloheteroalkyl rings in (XVII) and(XVIII) are optionally substituted with one or more groups selected fromhalo, CN, NO₂, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy;

[0057] or R⁴ and R⁵ together form a structure selected from Formula(XII) to (XVI):

[0058] wherein the aryl ring in Formula (XV) is optionally substitutedwith one or more groups selected from halo, CN, OH, C₁₋₆ alkyl, C₁₋₆alkoxy and —CO₂R³¹;

[0059] R¹⁰ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

[0060] R¹¹ is selected from hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl, or optionally, R¹¹ and either R¹⁶ or R¹⁷, together withthe atoms to which R¹¹ and either R¹⁶ or R¹⁷ are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring, optionally towhich is fused an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

[0061] R¹⁵ is independently selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

[0062] R¹⁶ and R¹⁷ are independently selected from hydrogen, alkylsubstituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,substituted carbomoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl or optionally, R¹⁶ andR¹⁷ together with the carbon atom to which R¹⁶ and R¹⁷ are attached forma cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring;

[0063] each R²⁰ and R²¹ is independently selected from hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl,alkylamino, substituted alkylamino, alklysulfinyl, substitutedalkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio,substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substitutedaryloxy, carbamoyl, substituted carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, substituted dialkylamino, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy,heteroaryloxy, and substituted heteroaryloxy, or optionally, when r is1, then R²⁰ and R²¹ together with the carbon atom to which each R²⁰ andR²¹ is attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring, or optionallywhen R²⁰ and R¹⁵ are present and are attached to adjacent atoms then R¹⁵and R²⁰ together with the atoms to which R¹⁵ and R²⁰ are attached form acycloheteroalkyl or substituted cycloheteroalkyl ring;

[0064] R²⁷ is selected from alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

[0065] R²⁸ and R²⁹ are independently selected from hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,substituted alkoxycarbonyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroalkyl, and substituted heteroalkyl; and

[0066] R³¹ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl;

[0067] with the provisos that

[0068] when X is —OR¹⁰, R¹ is hydrogen, and R⁴ and R⁵ are independentlyselected from hydrogen and C₁₋₁₉ alkyl, C₁₋₁₉ aryl or C₁₋₁₉ arylalkyl,then R¹⁰ is not hydrogen or C₁₋₆ alkyl; and

[0069] none of R¹, R⁴, R⁵, R¹⁰, R¹¹, R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹, R²⁷, R²⁸,R²⁹, and R³¹ comprise a bile acid moiety.

[0070] A second aspect provides compositions of compounds of carbidopaprodrugs and derivatives thereof. In certain embodiments, thecompositions comprise a carbidopa prodrug or a derivative thereof, or anenantiomer and stereoisomer of any of the foregoing, or apharmaceutically acceptable salt thereof, a hydrate thereof, or asolvate of any of the foregoing and a pharmaceutically acceptablediluent, carrier, excipient and/or adjuvant of any of the foregoing. Thechoice of diluent, carrier, excipient and/or adjuvant can depend upon,among other factors, the desired mode of administration.

[0071] A third aspect provides methods for treating Parkinson's disease.The methods comprise co-administering to a patient in need of suchtreatment a therapeutically effective amount of at least one offollowing combinations: i) levodopa and carbidopa prodrug; ii) levodopaand carbidopa derivative; iii) levodopa prodrug and carbidopa prodrug;iv) levodopa prodrug and carbidopa derivative; vi) a stereoisomer or anenantiomer of any of the foregoing; and vi) a pharmaceuticallyacceptable salt thereof, a hydrate thereof or a solvate of any of theforegoing, are included in the embodiments. In certain embodiments, theat least one combination is administered to the patient using asustained-release dosage form or device.

[0072] In certain embodiments, the carbidopa prodrug or derivativethereof can be released from the dosage form or device over a period ofat least 6 hours, in certain embodiments, over a period of at least 8hours, and in certain embodiments, over a period of at least 12 hours.Further, in certain embodiments, the dosage form or device can releasefrom 0 to 20% of the prodrug or derivative thereof in 0 to 2 hours, from20 to 50% of the prodrug or derivative thereof in 2 to 12 hours, from 50to 85% of the prodrug in 3 to 20 hours and greater than 75% of theprodrug or derivative thereof in 5 to 18 hours.

[0073] The oral sustained release dosage forms or devices used withcertain embodiments can take any form as long as the releasecharacteristics and pharmacokinetic profiles above are satisfied. Forexample, the dosage form can be in the form of an osmotic dosage form, aprodrug- or derivative-releasing polymer, prodrug- orderivative-releasing tiny timed-release pills, prodrug- orderivative-releasing lipids, prodrug- or derivative-releasing waxesand/or prodrug- or derivative-releasing beads.

[0074] A fourth aspect provides compositions for treating Parkinson'sdisease or hypertension in a patient in need of such treatment.

[0075] A fifth aspect provides methods for making carbidopa prodrugs andderivatives thereof, compositions of carbidopa prodrugs and derivativesthereof, methods of using carbidopa prodrugs and derivatives thereof,and methods of using compositions of carbidopa prodrugs and derivativesthereof for treating Parkinson's disease or hypertension.

Specific Embodiments

[0076] Definitions

[0077] Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations that may vary depending upon theproperties sought to be obtained. At the very least, and not as anattempt to limit the application of the doctrine of equivalents to thescope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

[0078] Notwithstanding that the numerical ranges and parameters settingforth the broad scope of the embodiments are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical values, however, inherently containcertain errors necessarily resulting form the standard deviation foundin their respective testing measurements.

[0079] To the extent the definitions of terms in the publications,patents, and patent applications incorporated herein by reference arenot the same as the definitions set forth in this specification, thedefinitions in this specification control for the entire specification,including the claims. Any other definitions in the publications,patents, and patent applications incorporated herein by reference thatare not explicitly provided in this specification apply only to theembodiments discussed in the publications, patents, and patentapplications incorporated herein by reference.

[0080] “Compounds” refers to compounds encompassed by generic formulaedisclosed herein, any subgenus of those generic formulae, and anyspecific compounds within those generic or subgeneric formulae. Thecompounds can be a specific specie, a subgenus or larger genusidentified either by their chemical structure and/or chemical name.Further, compounds also include substitutions or modifications of any ofsuch species, subgenuses or genuses, which are set forth herein. Whenthe chemical structure and chemical name conflict, the chemicalstructure is determinative of the identity of the compound. Thecompounds can contain one or more chiral centers and/or double bonds andtherefore, can exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers or diastereomers. Accordingly,the chemical structures within the scope of the specification encompassall possible enantiomers and stereoisomers of the illustrated compoundsincluding the stereoisomerically pure form (e.g., geometrically pure,enantiomerically pure or diastereomerically pure) and enantiomeric andstereoisomeric mixtures. Further, when partial structures of thecompounds are illustrated, asterisks indicate the point of attachment ofthe partial structure to the rest of the molecule. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan.

[0081] “Alkyl” refers to a saturated or unsaturated, branched,straight-chain or cyclic monovalent hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane, alkene or alkyne. Typical alkyl groups include, but are notlimited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propylssuch as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl;cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl; butyls such asbutan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like.

[0082] The term “alkyl” is specifically intended to include groupshaving any degree or level of saturation, i.e., groups havingexclusively single carbon-carbon bonds, groups having one or more doublecarbon-carbon bonds, groups having one or more triple carbon-carbonbonds and groups having mixtures of single, double and triplecarbon-carbon bonds. Where a specific level of saturation is intended,the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used. In certainembodiments, an alkyl group comprises from 1 to 20 carbon atoms.

[0083] “Alkanyl” refers to a saturated branched, straight-chain orcyclic alkyl group derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane. Typical alkanyl groups include,but are not limited to, methanyl; ethanyl; propanyls such aspropan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl; butanyls such asbutan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl; and the like.

[0084] “Alkenyl” refers to an unsaturated branched, straight-chain orcyclic alkyl group having at least one carbon-carbon double bond derivedby the removal of one hydrogen atom from a single carbon atom of aparent alkene. The group can be in either the cis or trans conformationabout the double bond(s). Typical alkenyl groups include, but are notlimited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl; and the like.

[0085] “Alkynyl” refers to an unsaturated branched, straight-chain orcyclic alkyl group having at least one carbon-carbon triple bond derivedby the removal of one hydrogen atom from a single carbon atom of aparent alkyne. Typical alkynyl groups include, but are not limited to,ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls suchas but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like.

[0086] “Alkylene” refers to a saturated or unsaturated, branched,straight-chain or cyclic divalent hydrocarbon group derived by theremoval of two hydrogen atoms from a parent alkane, alkene or alkyne.Typical alkylene groups include, but are not limited to methylene,ethylene, propylene, butylene; and the like.

[0087] “Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to, formyl, acetyl, cylcohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

[0088] “Acylamino” refers to a radical —NR′C(O)R, where R′ and R areeach independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein.Representative examples include, but are not limited to, formylamino,acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino,benzoylamino, benzylcarbonylamino and the like.

[0089] “Alkylamino” refers to a radical —NHR where R represents an alkylor cycloalkyl group as defined herein. Representative examples include,but are not limited to, methylamino, ethylamino, 1-methylethylamino,cyclohexyl amino and the like.

[0090] “Alkoxy” refers to a radical —OR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy andthe like.

[0091] “Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy isas defined herein.

[0092] “Alkylsulfonyl” refers to a radical —S(O)₂R where R is an alkylor cycloalkyl group as defined herein. Representative examples include,but are not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl and the like.

[0093] “Alkylsulfinyl” refers to a radical —S(O)R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like.

[0094] “Alkylthio” refers to a radical —SR where R is an alkyl orcycloalkyl group as defined herein that can be optionally substituted asdefined herein. Representative examples include, but are not limited to,methylthio, ethylthio, propylthio, butylthio, and the like.

[0095] “Amino” refers to the radical —NH₂.

[0096] “Aryl” refers to a monovalent aromatic hydrocarbon group derivedby the removal of one hydrogen atom from a single carbon atom of aparent aromatic ring system. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In certainembodiments, an aryl group comprises from 6 to 20 carbon atoms.

[0097] “Arylene” refers to a divalent aromatic hydrocarbon group derivedby removal of two hydrogen atoms from a parent aromatic ring system.

[0098] “Arylalkyl” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl group. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl and/or arylalkynyl is used. In certainembodiments, an arylalkyl group is (C₆-C₃₀) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₁₀)and the aryl moiety is (C₆-C₂₀).

[0099] “Arylalkylene” refers to a divalent acyclic alkyl group in whichone of the hydrogen atoms bonded to a carbon atom, typically a terminalor sp³ carbon atom is replaced with an aryl group.

[0100] “Arylalkyloxy” refers to an —O-arylalkyl group where arylalkyl isas defined herein.

[0101] “Aryloxycarbonyl” refers to a radical —C(O)—O-aryl where aryl isas defined herein.

[0102] “Bile acid moiety” refers to a moiety which has, or whichincludes, a structure of Formulae (A) or (B):

[0103] wherein each of D, E and F are independently H, OH or O—; whereinG is OH or O—; wherein J is COOH or CO—; and wherein at least one, andat most two, of D, E, F, G and J within a structure of Formulae (A) or(B) are O— or CO— and serve as point(s) of covalent bonding to anothermoiety or moieties.

[0104] “Carbamoyl” refers to the radical —C(O)N(R)₂ where each R groupis independently hydrogen, alkyl, cycloalkyl or aryl as defined herein,which can be optionally substituted as defined herein.

[0105] “Carboxy” refers to the radical —C(O)OH.

[0106] “Cyano” refers to the radical —CN.

[0107] “Cycloalkyl” refers to a saturated or unsaturated cyclic alkylgroup. Where a specific level of saturation is intended, thenomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typicalcycloalkyl groups include, but are not limited to, groups derived fromcyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In acertain embodiment, the cycloalkyl group is (C₃-C₁₀) cycloalkyl, or incertain embodiments (C₃-C₆) cycloalkyl.

[0108] “Cycloheteroalkyl” refers to a saturated or unsaturated cyclicalkyl group in which one or more carbon atoms (and any associatedhydrogen atoms) are independently replaced with the same or differentheteroatom. Typical heteroatoms to replace the carbon atom(s) include,but are not limited to, N, P, O, S, and Si. Where a specific level ofsaturation is intended, the nomenclature “cycloheteroalkanyl” or“cycloheteroalkenyl” is used. Typical cycloheteroalkyl groups include,but are not limited to, groups derived from epoxides, imidazolidine,morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine,quinuclidine, and the like.

[0109] “Cycloheteroalkyloxycarbonyl” refers to a radical —C(O)—OR whereR is cycloheteroalkyl is as defined herein.

[0110] “Dialkylamino” refers to a radical —NRR′ where R and R′independently represent an alkyl or cycloalkyl group as defined herein.Representative examples include, but are not limited to, dimethylamino,methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, and the like.

[0111] “Halo” refers to fluoro, chloro, bromo, or iodo.

[0112] “Heteroalkyloxy” refers to an —O-heteroalkyl group whereheteroalkyl is as defined herein.

[0113] “Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl” referto alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in whichone or more of the carbon atoms (and any associated hydrogen atoms) areeach independently replaced with the same or different heteroatomicgroups. Typical heteroatomic groups include, but are not limited to,—O—, —S—, —O—O', —S—S—, —O—S—, —NR′—, ═N—N═, —N═N—, —N═N—NR′—, —PH—,—P(O)₂—, —O—P(O)₂—, —S(O)—, —S(O)₂—, —SnH₂— and the like, wherein R′ ishydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl or substituted aryl.

[0114] “Heteroaryl” refers to a monovalent heteroaromatic group derivedby the removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. In certain embodiments, theheteroaryl group is between 5-20 membered heteroaryl, and in otherembodiments is between 5-10 membered heteroaryl. In certain embodimentsheteroaryl groups are those derived from thiophene, pyrrole,benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole,oxazole and pyrazine.

[0115] “Heteroaryloxycarbonyl” refers to a radical —C(O)—OR where R isheteroaryl as defined herein.

[0116] “Heteroarylalkyl” refers to an acyclic alkyl group in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp³ carbon atom, is replaced with a heteroaryl group. Where specificalkyl moieties are intended, the nomenclature heteroarylalkanyl,heteroarylalkenyl and/or heteroarylalkynyl is used. In certainembodiments, the heteroarylalkyl group is a 6-30 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of theheteroarylalkyl is 1-10 membered and the heteroaryl moiety is a5-20-membered heteroaryl.

[0117] “Leaving group” has the meaning conventionally associated with itin synthetic organic chemistry, i.e., an atom or a group capable ofbeing displaced by a nucleophile and includes halo (such as chloro,bromo, and iodo), acyloxy (e.g., acetoxy, benzoyloxy), mesyloxy,tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g.,2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the like.

[0118] “Pharmaceutically acceptable” refers to approved or approvable bya regulatory agency of the Federal or a state government or listed inthe U.S. Pharmacopeia or other generally recognized pharmacopeia for usein animals, and more particularly in humans.

[0119] “Pharmaceutically acceptable salt” refers to a salt of a compoundthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine,dicyclohexylamine and the like.

[0120] “Pharmaceutically acceptable vehicle” refers to a diluent,adjuvant, excipient or carrier with which a compound is administered.

[0121] “Extended release” refers to dosage forms that provide for thedelayed, slowed, over a period of time, continuous, discontinuous, orsustained release of the compounds.

[0122] “Patient” includes mammals and humans. The terms “human” and“patient” are used interchangeably herein.

[0123] “Prodrug” refers to a derivative of a drug molecule that requiresa transformation within the body to release the active drug. Prodrugsare frequently (though not necessarily) pharmacologically inactive untilconverted to the parent drug.

[0124] “Promoiety” refers to a form of protecting group that when usedto mask a functional group within a drug molecule converts the drug intoa prodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

[0125] “Protecting group” refers to a grouping of atoms that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting groups can be found in Green etal., “Protective Groups in Organic Chemistry”, (Wiley, 2^(nd) ed. 1991)and Harrison et al., “Compendium of Synthetic Organic Methods”, Vols.1-8 (John Wiley and Sons, 1971-1996). Representative amino protectinggroups include, but are not limited to, formyl, acetyl, trifluoroacetyl,benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”),trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityland substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

[0126] “Substituted” refers to a group in which one or more hydrogenatoms are each independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,—X, —R³³, —O⁻, ═O, —OR³³, —SR³³, —S⁻, ═S, —NR³³R³⁴, ═NR³³, —CX₃, —CF₃,—CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R³³,—OS(O₂)O⁻, —OS(O)₂R³³, —P(O)(O⁻)₂, —P(O)(OR³³)(O⁻), —OP(O)(OR³³)(OR³⁴),—C(O)R³³, —C(S)R³³, —C(O)OR³³, —C(O)NR³³R³⁴, —C(O)O⁻, —C(S)OR³³,—NR³⁵C(O)NR³³R³⁴, —NR³⁵C(S)NR³³R³⁴, —NR³⁵C(NR³³)NR³³R³⁴ and—C(NR³³)NR³³R³⁴, where each X is independently a halogen; each R³³ andR³⁴ are independently hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —NR³⁵R³⁶,—C(O)R³⁵ or —S(O)₂R³⁵ or optionally R³³ and R³⁴ together with the atomto which they are both attached form a cycloheteroalkyl or substitutedcycloheteroalkyl ring; and R³⁵ and R³⁶ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl.

[0127] “Treating” or “treatment” of any disease or disorder refers toarresting or ameliorating a disease or disorder, reducing the risk ofacquiring a disease or disorder, reducing the development of a diseaseor disorder or at least one of the clinical symptoms of the disease ordisorder, or reducing the risk of developing a disease or disorder or atleast one of the clinical symptoms of a disease or disorder. “Treating”or “treatment” also refers to inhibiting the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both,and inhibit at least one physical parameter which may not be discernibleto the patient. Further, “treating” or “treatment” refers to delayingthe onset of the disease or disorder or at least symptoms thereof in apatient which may be exposed to or predisposed to a disease or disordereven though that patient does not yet experience or display symptoms ofthe disease or disorder.

[0128] “Therapeutically effective amount” refers to the amount of acompound that, when administered to a patient for treating a disease ordisorder, is sufficient to affect such treatment for the disease ordisorder. The “therapeutically effective amount” will vary depending onthe compound, the disease or disorder and its severity and the age andweight of the patient to be treated.

[0129] “Cleave” refers to breakage of chemical bonds and is not limitedto chemical or enzymatic reactions or mechanisms unless clearlyindicated by the context.

[0130] Thus, the development of levodopa prodrugs and/or carbidopaprodrugs and derivatives thereof that can be efficiently absorbedthroughout the gastrointestinal tract, including the colon, is highlydesirable.

[0131] Reference will now be made in detail to certain embodiments.

Compounds

[0132] Compounds include carbidopa prodrugs and other derivatives towhich promoieties have been attached. In certain embodiments, compoundsinclude carbidopa derivatives of Formula (I):

[0133] a stereoisomer thereof, an enantiomer thereof, a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing, wherein:

[0134] X is selected from —OR¹⁰ and moieties of Formulae (II) and (III):

[0135] where:

[0136] r is an integer from 1 to 6;

[0137] Q is O or —NR⁵;

[0138] R¹ is selected from hydrogen and the structure of Formula (IX):

[0139] R⁴ and R⁵ are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroalkyl, substitutedheteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,—C(O)OR²⁷, —C(O)R²⁷, —(CR¹⁶R¹⁷)OC(O)R¹¹, and moieties of Formulae (XVII)and (XVIII):

[0140] wherein o is 1-3, and the cycloheteroalkyl rings in (XVII) and(XVIII) are optionally substituted with one or more groups selected fromhalo, CN, NO₂, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy;

[0141] or R⁴ and R⁵ together form a structure selected from Formulae(XII) to (XVI):

[0142] wherein the aryl ring in Formula (XV) is optionally substitutedwith one or more groups selected from halo, CN, OH, C₁₋₆ alkyl, C₁₋₆alkoxy, and —CO₂R³¹;

[0143] R¹⁰ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

[0144] R¹¹ is selected from hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl, or optionally, R¹¹ and either R¹⁶ or R¹⁷, together withthe atoms to which R¹¹ and either R¹⁶ or R¹⁷ are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring, optionally towhich is fused an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

[0145] R¹⁵ is independently selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;

[0146] R¹⁶ and R¹⁷ are independently selected from hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,substituted carbomoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl or optionally, R¹⁶ andR¹⁷ together with the carbon atom to which R¹⁶ and R¹⁷ are attached forma cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring;

[0147] each R²⁰ and R²¹ is independently selected from hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl,alkylamino, substituted alkylamino, alklysulfinyl, substitutedalkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio,substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substitutedaryloxy, carbamoyl, substituted carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, substituted dialkylamino, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy,heteroaryloxy, and substituted heteroaryloxy, or optionally, when r is1, then R²⁰ and R²¹ together with the carbon atom to which each R²⁰ andR²¹ is attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring, or optionallywhen R²⁰ and R¹⁵ are present and are attached to adjacent atoms then R¹⁵and R²⁰ together with the atoms to which R¹⁵ and R²⁰ are attached form acycloheteroalkyl or substituted cycloheteroalkyl ring;

[0148] R²⁷ is selected from alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

[0149] R²⁸ and R²⁹ are independently selected from hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,substituted alkoxycarbonyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroalkyl, and substituted heteroalkyl; and

[0150] R³¹ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl;

[0151] with the provisos that when X is —OR¹⁰, R¹ is hydrogen, and R⁴and R⁵ are independently selected from hydrogen and C₁₋₁₉ alkyl, C₁₋₁₉aryl or C₁₋₁₉ arylalkyl, then R¹⁰ is not hydrogen or C₁₋₆ alkyl; and

[0152] none of R¹, R⁴, R⁵, R¹⁰, R¹¹, R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹, R²⁷, R²⁸,R²⁹, and R³¹ comprise a bile acid moiety.

[0153] In certain embodiments, the compounds are represented by Formula(Ia) shown below:

[0154] and stereoisomers thereof, enantiomers thereof, pharmaceuticallyacceptable salts thereof, hydrates thereof, or solvates of any of theforegoing, wherein:

[0155] R¹ is selected from hydrogen, and the structure of Formula (IX):

[0156] R⁴ and R⁵ are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroalkyl, substitutedheteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,—C(O)OR²⁷, —C(O)R²⁷, —(CR¹⁶R¹⁷)OC(O)R¹¹, and moieties of Formulae (XVII)and (XVIII):

[0157] wherein o is 1-3, and the cycloheteroalkyl rings in (XVII) and(XVIII) are optionally substituted with one or more groups selected fromhalo, CN, NO₂, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy;

[0158] or R⁴ and R⁵ together form a structure selected from Formulae(XII) to (XVI):

[0159] wherein the aryl ring in Formula (XV) is optionally substitutedwith one or more groups selected from halo, CN, OH, C₁₋₆ alkyl, C₁₋₆alkoxy, and —CO₂R³¹;

[0160] R¹⁰ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

[0161] R¹¹ is selected from hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, alkoxy,heteroaryl, substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl, or optionally, R¹¹ and either R¹⁶ or R¹⁷, together withthe atoms to which R¹¹ and either R¹⁶ or R¹⁷ are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring, optionally towhich is fused an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

[0162] R¹⁶ and R¹⁷ are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroarylalkyl, and substitutedheteroarylalkyl or optionally, R¹⁶ and R¹⁷ together with the carbon atomto which they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring;

[0163] R²⁷ is selected from alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

[0164] R²⁸ and R²⁹ are independently selected from hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,substituted alkoxycarbonyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroalkyl, and substituted heteroalkyl; and

[0165] R³¹ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, arylalkyl, heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl;

[0166] with the provisos that when R¹ is hydrogen, and R⁴ and R⁵ areindependently selected from hydrogen, C₁₋₁₉ alkyl, C₁₋₁₉ aryl or C₁₋₁₉arylalkyl, then R¹⁰ is not hydrogen or C₁₋₆ alkyl; and

[0167] none of R¹, R⁴, R⁵, R¹⁰, R¹¹, R¹⁵, R¹⁶, R¹⁷, R²⁷, R²⁸, R²⁹, andR³¹ comprises a bile acid moiety.

[0168] In certain embodiments of a compound of Formula (Ia):

[0169] R⁴ and R⁵ are independently moieties having the structures ofFormulae (XVII) and (XVIII):

[0170] In certain embodiments of a compound of Formula (Ia), R¹ ishydrogen.

[0171] In certain embodiments of a compound of Formula (Ia), R¹ is amoiety comprising Formula (IX).

[0172] In certain embodiments of a compound of Formula (Ia), R⁴ and R⁵are independently selected from hydrogen, alkanyl, substituted alkanyl,arylalkanyl, substituted arylalkanyl, heteroarylalkanyl, substitutedheteroarylalkanyl, cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl, and substituted cycloheteroalkanyl. In certainembodiments of a compound of Formula (Ia), R⁴ and R⁵ are independentlyselected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, benzyl, and pyridyl, where the aryl rings of the benzyl andpyridyl groups are optionally substituted with one or more substituentsselected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.

[0173] In certain embodiments of a compound of Formula (Ia), R⁴ and R⁵are independently selected from hydrogen, —C(O)OR²⁷, and —C(O)R²⁷. Incertain embodiments, R⁴ and R⁵ are both independently —C(O)OR²⁷ or—C(O)R²⁷. In certain embodiments, R²⁷ is selected from C₁₋₁₀ alkyl,substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl,C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.

[0174] In certain embodiments, R²⁷ is selected from alkanyl, substitutedalkanyl, cycloalkanyl, substituted cycloalkanyl, arylalkanyl,substituted arylalkanyl, heteroarylalkanyl and substitutedheteroarylalkanyl. In certain embodiments, R²⁷ is selected from methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and benzyl where thearyl ring of the benzyl group is optionally substituted with one or moresubstituents selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,and —CO₂R³¹.

[0175] In certain embodiments, R²⁷ is selected from aryl, substitutedaryl, heteroaryl, and substituted heteroaryl. In certain embodiments,R²⁷ is selected from phenyl, pyridyl, furyl, and thienyl, the aromaticrings of which are optionally substituted with one or more substituentsselected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.

[0176] In certain embodiments, R²⁷ is selected from C₁₋₁₀ alkyl,substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.

[0177] In certain embodiments of a compound of Formula (Ia), R⁴ and R⁵are independently selected from hydrogen, and —(CR¹⁶R¹⁷)OC(O)R¹¹. Incertain embodiments, R⁴ and R⁵ are both independently—(CR¹⁶R¹⁷)OC(O)R¹¹.

[0178] In certain embodiments of a compound of Formula (Ia), R⁴ and R⁵are independently selected from —(CR¹⁶R¹⁷)OC(O)R¹¹R¹¹, and—(CR¹⁶R¹⁷)OC(O)R¹¹ wherein R¹¹ is selected from hydrogen, C₁₋₁₀ alkyl,substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₁₋₁₅ alkoxy,and substituted C₁₋₁₅ alkoxy.

[0179] In certain embodiments of a compound of Formula (Ia), R⁴ and R⁵are independently selected from —(CR¹⁶R¹⁷)OC(O)R¹¹R¹¹, and—(CR¹⁶R¹⁷)OC(O)R¹¹ wherein R¹⁶ and R¹⁷ are independently selected fromhydrogen, C₁₋₁₆ alkyl, substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substitutedC₅₋₈ aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀ arylalkyl.

[0180] In certain embodiments of a compound of Formula (Ia), R⁴ and R⁵together with the atoms to which they are attached are incorporated intoa benzo-fused heterocyclic ring of Formula (XIV).

[0181] In certain embodiments of a compound of Formula (Ia), R¹⁰ isselected from hydrogen, alkanyl, substituted alkanyl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl, substituted cycloheteroalkanyl, heteroarylalkanyl,and substituted heteroarylalkanyl. In certain embodiments, R¹⁰ isselected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenoxyethyl, carboxymethyl, carboxyethyl, carboxypropyl,carboxybutyl, and benzyl, all of which are optionally substituted withone or more substituents selected from halo, CN, NO₂, OH, C₁₋₆ alkyl,C₁₋₆ alkoxy, and —CO₂R³¹.

[0182] In certain embodiments of a compound of Formula (Ia), R¹⁰ isselected from hydrogen, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl. In certain embodiments, R¹⁰ is selected fromphenyl and substituted phenyl, where the one or more substituents areselected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.

[0183] In certain embodiments of a compound of Formula (Ia), R¹⁰ isselected from C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl,substituted C₅₋₈ aryl, —R³²OC(O)R³⁷, and —R³²OC(O)OR³⁷, where where R³²is selected from C₁₋₁₀ alkylene, substituted C₁₋₁₀ alkylene, C₅₋₈arylene, substituted C₅₋₈ arylene, C₆₋₁₀ arylalkylene, and substitutedC₆₋₁₀ arylalkylene, and R³⁷ is selected from C₁₋₁₀ alkyl, substitutedC₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, andsubstituted C₆₋₁₀ arylalkyl.

[0184] In certain embodiments of a compound of Formula (Ia), R¹¹ isselected from alkanyl, substituted alkanyl, alkenyl, substitutedalkenyl, arylalkanyl, substituted arylalkanyl, arylalkenyl, substitutedarylalkenyl, cycloalkanyl, substituted cycloalkanyl, heteroarylalkanyl,and substituted heteroarylalkanyl. In certain embodiments, R¹¹ isselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and styryl, where the aryl ring of the styryl group is optionallysubstituted with one or more substituents selected from halo, CN, NO₂,OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.

[0185] In certain embodiments of a compound of Formula (Ia), R¹¹ isselected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl. In certain embodiments, R¹¹ is selected from phenyl,pyridyl, indolyl, furyl, imidazolyl and oxazolyl, the aromatic rings ofwhich are optionally substituted with one or more substituents selectedfrom halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.

[0186] In certain embodiments of a compound of Formula (Ia), R¹¹ isselected from hydrogen, C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl,substituted C₅₋₈ aryl, C₁₋₁₅ alkoxy, and substituted C₁₋₁₅ alkoxy.

[0187] In certain embodiments of a compound of Formula (Ia), R¹¹ isselected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclobutoxy,cyclopentyloxy, cyclohexyloxy, 2,6-dimethylcyclohexyloxy, fenchyloxy,and adamantyloxy.

[0188] In certain embodiments of a compound of Formula (Ia), R¹¹ andeither R¹⁶ or R¹⁷, together with the atoms to which R¹¹ and either R¹⁶or R¹⁷ are attached, form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring, optionally towhich is fused an aryl, substituted aryl, heteroaryl or substitutedheteroaryl ring.

[0189] In certain embodiments of a compound of Formula (Ia), R¹⁶ and R¹⁷are independently selected from hydrogen, alkanyl, substituted alkanyl,cycloalkanyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, arylalkanyl, and substituted arylalkanyl. In certainembodiments, R¹⁶ and R¹⁷ are independently selected from hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, and benzyl, where the aryl ring of thephenyl and the benzyl groups is optionally substituted with one or moresubstituents selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,and —CO₂R³¹.

[0190] In certain embodiments of a compound of Formula (Ia), R¹⁶ and R¹⁷together with the carbon atom to which they are attached form acycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl orsubstituted cycloheteroalkanyl ring. In certain embodiments, R¹⁶ and R¹⁷together with the carbon atom to which they are attached form acyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

[0191] In certain embodiments of a compound of Formula (Ia), R¹⁶ and R¹⁷are independently selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, andsubstituted C₆₋₁₀ arylalkyl.

[0192] In certain embodiments of a compound of Formula (Ia), R²⁸ and R²⁹are independently selected from hydrogen, alkanyl, aryl, andalkoxycarbonyl. In certain embodiments, R²⁸ and R²⁹ are independentlyselected from hydrogen, methyl, ethyl, phenyl, methoxycarbonyl, andethoxycarbonyl. In certain embodiments, R²⁸ and R³⁹ are both hydrogen.

[0193] In certain embodiments of a compound of Formula (Ia), R³¹ ishydrogen or C₁₋₈ alkyl or cycloalkyl. In certain embodiments, R³¹ ishydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0194] In certain embodiments of a compound of Formula (Ia), R¹ ishydrogen, and R¹⁰ is selected from C₇₋₁₀ alkyl, substituted C₇₋₁₀ alkyl,C₅₋₈ aryl, substituted C₅₋₈ aryl, —R³²OC(O)R³⁷, and —R³²OC(O)OR³⁷, whereR³² is selected from C₁₋₁₀ alkylene, substituted C₁₋₁₀ alkylene, C₅₋₈arylene, substituted C₅₋₈ arylene, C₆₋₁₀ arylalkylene, and substitutedC₆₋₁₀ arylalkylene, and R³⁷ is selected from C₁₋₁₀ alkyl, substitutedC₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, andsubstituted C₆₋₁₀ arylalkyl.

[0195] In certain embodiments of a compound of Formula (Ia), R¹ is amoiety of Formula (IX), and R¹⁰ is selected from C₇₋₁₀ alkyl,substituted C₇₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, —R³²OC(O)R³⁷,and —R³²OC(O)OR³⁷, where R³² is selected from C₁₋₁₀ alkylene,substituted C₁₋₁₀ alkylene, C₅₋₈ arylene, substituted C₅₋₈ arylene,C₆₋₁₀ arylalkylene, and substituted C₆₋₁₀ arylalkylene, and R³⁷ isselected from C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl,substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀ arylalkyl.

[0196] In certain embodiments, compounds of Formula (I) are representedby Formulae (Ib) or (Ic) below:

[0197] and stereoisomers thereof, enantiomers thereof, pharmaceuticallyacceptable salts thereof, hydrates thereof, or solvates of any of theforegoing, wherein:

[0198] Q is O or —NR¹⁵;

[0199] r is an integer from 1 to 6;

[0200] R¹ is selected from hydrogen, and a moiety of Formula (IX):

[0201] R⁴ and R⁵ are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroalkyl, substitutedheteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl,substituted cycloalkyl, —C(O)R²⁷, —C(O)R²⁷, —(CR¹⁶R¹⁷)OC(O)R¹¹, andmoieties of Formulae (XVII) and (XVIII):

[0202] wherein o is 1-3, and the cycloheteroalkyl rings in (XVII) and(XVIII) are optionally substituted with one or more groups selected fromhalo, CN, NO₂, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy;

[0203] or R⁴ and R⁵ are independently moieties having the structures ofFormulae (XII) to (XVI):

[0204] wherein the aryl ring in Formula (XV) is optionally substitutedwith one or more groups selected from halo, CN, OH, C₁₋₆ alkyl, C₁₋₆alkoxy, and —CO₂R³¹;

[0205] R¹⁰ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

[0206] R¹¹ is selected from hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, aryl, substituted aryl, aryloxy, substitutedaryloxy, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, heteroalkyl,substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl, or optionally, R¹¹ and either R¹⁶ or R¹⁷, together withthe atoms to which R¹¹ and either R¹⁶ or R¹⁷ are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring, optionally towhich is fused an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

[0207] R¹⁵ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, and substituted arylalkyl;

[0208] R¹⁶ and R¹⁷ are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroarylalkyl, and substitutedheteroarylalkyl or optionally, R¹⁶ and R¹⁷ together with the carbon atomto which they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring;

[0209] each R²⁰ and R²¹ is independently selected from hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl,alkylamino, substituted alkylamino, alklysulfinyl, substitutedalkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio,substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substitutedaryloxy, carbamoyl, substituted carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,dialkylamino, substituted dialkylamino, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy,heteroaryloxy, and substituted heteroaryloxy, or optionally, when r is1, then R²⁰ and R²¹ together with the carbon atom to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring, or optionally when R²⁰ and R¹⁵ arepresent and are attached to adjacent atoms then R¹⁵ and R²⁰ togetherwith the atoms to which they are attached form a cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

[0210] R²⁷ is selected from alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

[0211] R²⁸ and R²⁹ are independently selected from hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl,substituted alkoxycarbonyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroalkyl, and substituted heteroalkyl; and

[0212] R³¹ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl;

[0213] with the proviso that none of R¹, R⁴, R⁵, R¹⁰, R¹¹, R¹⁵, R¹⁶,R¹⁷, R²⁰, R²¹, R²⁷, R²⁸, R²⁹, and R³¹ comprise a bile acid moiety.

[0214] In certain embodiments of a compound of Formulae (Ib) or (Ic), R⁴and R⁵ are independently selected moieties from Formulae (XVII), and(XVIII).

[0215] In certain embodiments of a compound of Formula (Ic), Q is O.

[0216] In certain embodiments of a compound of Formula (Ic), Q is —NR¹⁵.

[0217] In certain embodiments of a compound of Formulae (Ib) or (Ic), R¹is hydrogen.

[0218] In certain embodiments of a compound of Formulae (Ib) or (Ic), R¹is a moiety of Formula (IX).

[0219] In certain embodiments of a compound of Formulae (Ib) or (Ic), R⁴and R⁵ are independently selected from hydrogen, alkanyl, substitutedalkanyl, arylalkanyl, substituted arylalkanyl, heteroarylalkanyl,substituted heteroarylalkanyl, cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl, and substituted cycloheteroalkanyl. In certainembodiments, R⁴ and R⁵ are independently selected from hydrogen, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,cyclopentyl, cyclohexyl, benzyl, and pyridyl, where the aryl rings ofthe benzyl and pyridyl groups are optionally substituted with one ormore substituents selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆alkoxy, and —CO₂R³¹.

[0220] In certain embodiments of a compound of Formulae (Ib) or (Ic), R⁴and R⁵ are independently selected from hydrogen, —C(O)OR²⁷, and—C(O)R²⁷. In certain embodiments of a compound of Formulae (Ib) or (Ic),R⁴ and R⁵ are independently selected from hydrogen, —C(O)OR²⁷, and—C(O)OR27, wherein R²⁷ is selected from C₁₋₁₀ alkyl, substituted C ₁₋₁₀alkyl, C₅₋₈ aryl, C₅₋₈substituted aryl, C₆₋₁₀ arylalkyl, and substitutedC₆₋₁₀ arylalkyl.

[0221] In certain embodiments, R⁴ and R⁵ are both independently—C(O)OR²⁷ or —C(O)R²⁷. In certain embodiments, R⁴ and R⁵ are bothindependently —C(O)OR²⁷ or —C(O)R²⁷ where R²⁷ is selected from C₁₋₁₀alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, C₅₋₈ substituted aryl, C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.

[0222] In certain embodiments, R⁴ and R⁵ are both independently—C(O)OR²⁷ or —C(O)R²⁷ where R²⁷ is selected from alkanyl, substitutedalkanyl, cycloalkanyl, substituted cycloalkanyl, arylalkanyl,substituted arylalkanyl, heteroarylalkanyl, and substitutedheteroarylalkanyl. In certain embodiments, R²⁷ is selected from methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and benzyl, where thearyl ring of the benzyl group is optionally substituted with one or moresubstituents selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,and —CO₂R³¹.

[0223] In certain embodiments, R²⁷ is selected from aryl, substitutedaryl, heteroaryl, and substituted heteroaryl. In certain embodiments,R²⁷ is selected from phenyl, pyridyl, furyl, and thienyl, the aromaticrings of which are optionally substituted with one or more substituentsselected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.

[0224] In certain embodiments of a compound of Formulae (Ib) or (Ic), R⁴and R⁵ are independently selected from hydrogen and —(CR¹⁶R ¹⁷)OC(O)R¹¹.In certain embodiments of a compound of Formulae (Ib) or (Ic), R⁴ and R⁵are independently selected from hydrogen and —(CR ¹⁶R ¹⁷)OC(O)R¹¹wherein R¹¹ is selected from hydrogen, C₁₋₁₀ alkyl, substituted C₁₋₁₀alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₁₋₁₅ alkoxy, and substitutedC₁₋₁₅ alkoxy. In certain embodiments of a compound of Formulae (Ib) or(Ic), R⁴ and R⁵ are independently selected from hydrogen and—(CR¹⁶R¹⁷)OC(O)R¹¹ wherein R¹⁶ and R¹⁷ are independently selected fromhydrogen, C₁₋₆ alkyl, substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substitutedC₅₋₈ aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀ arylalkyl.

[0225] In certain embodiments of a compound of Formulae (Ib) or (Ic), R⁴and R⁵ are both independently —(CR¹⁶R₁₇)OC(O)R¹¹. In certainembodiments, R⁴ and R⁵ are both independently —(CR¹⁶R¹⁷)OC(O)R¹¹ whereinR¹¹ is selected from hydrogen, C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl,C₅₋₈ aryl, substituted C₅₋₈ aryl, C₁₋₁₅, alkoxy, and substituted C₁₋₁₅alkoxy. In certain embodiments, R⁴ and R⁵ are both independently—(CR¹⁶R¹⁷)OC(O)R¹¹ wherein R¹⁶ and R¹⁷ are independently selected fromhydrogen, C¹⁻¹⁶ alkyl, substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substitutedC₅₋₈ aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀ arylalkyl.

[0226] In certain embodiments of a compound of Formula (Ic), R¹⁰ isselected from hydrogen, alkanyl, substituted alkanyl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl, substituted cycloheteroalkanyl, heteroarylalkanyl,and substituted heteroarylalkanyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl. In certain embodiments, R¹⁰ is selected fromhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopentyl, cyclohexyl, and benzyl, where the aryl ring ofthe benzyl group is optionally substituted with one or more substituentsselected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.In certain embodiments, R¹⁰ is hydrogen, methyl or ethyl.

[0227] In certain embodiments of a compound of Formula (Ic), R¹⁰ isselected from hydrogen, C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl,and substituted C₅₋₈ aryl.

[0228] In certain embodiments of a compound of Formula (Ib), R¹¹ isselected from alkanyl, substituted alkanyl, alkenyl, substitutedalkenyl, arylalkanyl, substituted arylalkanyl, arylalkenyl, substitutedarylalkenyl, cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl,substituted cycloheteroalkanyl, heteroarylalkanyl, and substitutedheteroarylalkanyl. In certain embodiments, R¹¹ is selected from methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andstyryl, where the aryl ring of the styryl group is optionallysubstituted with one or more substituents are selected from halo, CN,NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.

[0229] In certain embodiments of a compound of Formula (Ib), R¹¹ isselected from aryl, substituted aryl, heteroaryl, and substitutedheteroaryl. In certain embodiments, R¹¹ is selected from phenyl,pyridyl, indolyl, furyl, imidazolyl, and oxazolyl, the aromatic rings ofwhich are optionally substituted with one or more substituents selectedfrom halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.

[0230] In certain embodiments of a compound of Formula (Ib), R¹¹ isselected from hydrogen, C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl,substituted C₅₋₈ aryl, C₁₋₁₅ alkoxy, and substituted C₁₋₁₅ alkoxy.

[0231] In certain embodiments of a compound of Formula (Ib), R¹¹ isselected from alkoxy, and cycloalkoxy. In certain embodiments, R¹¹ isselected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclobutoxy,cyclopentyloxy, cyclohexyloxy, 2,6-dimethylcyclohexyloxy, fenchyloxy,and adamantyloxy.

[0232] In certain embodiments of a compound of Formula (Ib), R¹¹ andeither R¹⁶ or R¹⁷, together with the atoms to which R¹¹ and either R¹⁶or R¹⁷ are attached, form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring, to which an aryl,substituted aryl, heteroaryl or substituted heteroaryl ring isoptionally fused to the cycloheteroalkyl or substituted cycloheteroalkylring.

[0233] In certain embodiments of a compound of Formulae (Ia), R¹ ishydrogen, R⁴ and R⁵ are each C(O)R²⁷, R¹⁰ is C₁₋₁₄ alkyl, and R²⁷comprises C₁₋₄ alkyl.

[0234] In certain embodiments of a compound of Formulae (Ia), R¹ ishydrogen, R⁴ and R⁵ are each C(O)R²⁷, R¹⁰ is C₁₋₄ alkyl, and R²⁷ istert-butyl.

[0235] In certain embodiments of a compound of Formulae (Ia), R¹ ishydrogen, R⁴ and R⁵ are each C(O)R²⁷, R¹⁰ is methyl or ethyl, and R²⁷comprises C₁₋₄ alkyl.

[0236] In certain embodiments of a compound of Formula (Ib), R¹ ishydrogen, R⁴ and R⁵ are each C(O)OR²⁷, R¹⁶ is hydrogen, R²⁷ is ethyl,R¹¹ is selected from C₁₋₁₄ alkyl, C₁₋₄ alkoxy, cyclohexyloxy,2,6-dimethylcyclohexyloxy, fenchyloxy, and adamantyloxy, and R¹⁷ isselected from hydrogen, and C₁₋₄ alkyl. In certain embodiments of acompound of Formula (Ib), R¹ is hydrogen, R⁴ and R⁵ are each C(O)OR²⁷,R¹⁶ is hydrogen, R²⁷ is ethyl, R¹¹ is selected from C₁₋₄ alkyl, C ₁₋₄alkoxy, cyclohexyloxy, 2,6-dimethylcyclohexyloxy, fenchyloxy, andadamantyloxy, and R¹⁷ is selected from hydrogen, and methyl.

[0237] In certain embodiments of a compound of Formula (Ib), R¹ ishydrogen, R⁴ and R⁵ are each C(O)R²⁷, R¹⁶ is hydrogen, R²⁷ is isopropyl,R¹¹ is selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, cyclohexyloxy,2,6-dimethylcyclohexyloxy, fenchyloxy, and adamantyloxy, and R¹⁷ isselected from hydrogen, and C₁₋₄ alkyl. In certain embodiments of acompound of Formula (Ib), R¹ is hydrogen, R⁴ and R⁵ are each C(O)R²⁷,R¹⁶ is hydrogen, R²⁷ is isopropyl, R¹¹ is selected from C₁₋₄ alkyl, C₁₋₄alkoxy, cyclohexyloxy, 2,6-dimethylcyclohexyloxy, fenchyloxy, andadamantyloxy, and R¹⁷ is selected from hydrogen, and methyl.

[0238] In certain embodiments of a compound of Formula (Ib), R¹ ishydrogen, R⁴ and R⁵ are each C(O)R²⁷, R¹⁶ is hydrogen, R²⁷ istert-butyl, R¹¹ is selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, cyclohexyloxy,2,6-dimethylcyclohexyloxy, fenchyloxy, and adamantyloxy, and R¹⁷ isselected from hydrogen, and C₁₋₄ alkyl. In certain embodiments of acompound of Formula (Ib), R¹ is hydrogen, R⁴ and R⁵ are each C(O)R²⁷,R¹⁶ is hydrogen, R²⁷ is tert-butyl, R¹¹ is selected from C ₁₋₄ alkyl,C₁₋₄ alkoxy, cyclohexyloxy, 2,6-dimethylcyclohexyloxy, fenchyloxy, andadamantyloxy, and R¹⁷ is selected from hydrogen, and methyl.

[0239] In certain embodiments of a compound of Formula (Ic), R¹⁵ ishydrogen.

[0240] In certain embodiments of a compound of Formula (Ic), R¹⁵ isselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, andsec-butyl. In certain embodiments, R¹⁵ is methyl.

[0241] In certain embodiments of a compound of Formulae (Ib) or (Ic),R¹⁶ and R¹⁷ are independently selected from hydrogen, alkanyl,substituted alkanyl, cycloalkanyl, substituted cycloalkanyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, arylalkanyl, andsubstituted arylalkanyl. In certain embodiments, R¹⁶ and R¹⁷ areindependently selected from hydrogen, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, and benzyl. In certain embodiments, R¹⁶is hydrogen and R¹⁷ is selected from hydrogen, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and benzyl.

[0242] In certain embodiments of a compound of Formulae (Ib) or (Ic),R¹⁶ and R¹⁷ together with the carbon atom to which they are attachedform a cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl orsubstituted cycloheteroalkanyl ring. In certain embodiments, R¹⁶ and R¹⁷together with the carbon atom to which they are attached form acyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

[0243] In certain embodiments of a compound of Formulae (Ib) or (Ic),R¹⁶ and R¹⁷ are independently selected from hydrogen, C₁₋₁₆ alkyl,substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.

[0244] In certain embodiments of a compound of Formula (Ic), each R²⁰and R²¹ is independently selected from hydrogen, alkanyl, substitutedalkanyl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, substitutedcycloalkanyl, cycloheteroalkanyl, substituted cycloheteroalkanyl, halo,heteroalkanyl, substituted heteroalkanyl, heteroarylalkanyl, andsubstituted heteroarylalkanyl. In certain embodiments, each R²⁰ and R²¹is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or benzyl.

[0245] In certain embodiments of a compound of Formula (Ic), each R²⁰and R²¹ is independently selected from hydrogen, alkanyl, substitutedalkanyl, arylalkanyl, substituted arylalkanyl, alkoxy, substitutedalkoxy, alkylamino, substituted alkylamino, aryloxy, substitutedaryloxy, dialkylamino, substituted dialkylamino, heteroalkyloxy,substituted heteroalkyloxy, heteroaryloxy, and substitutedheteroaryloxy. In certain embodiments, each R²⁰ and R²¹ is independentlyselected from hydrogen, alkoxy, alkylamino, aryloxy, dialkylamino orheteroalkyloxy.

[0246] In certain embodiments of a compound of Formula (Ic), each R²⁰and R²¹ is independently selected from hydrogen, alkanyl, substitutedalkanyl, arylalkanyl, substituted arylalkanyl, acyl, substituted acyl,alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, and substitutedcarbamoyl. In certain embodiments, each R²⁰ and R²¹ is hydrogen, acyl,substituted acyl, alkoxycarbonyl, carbamoyl or substituted carbamoyl.

[0247] In certain embodiments of a compound of Formula (Ic), each R²⁰and R²¹ is independently selected from hydrogen, alkanyl, substitutedalkanyl, arylalkanyl, substituted arylalkanyl, aryl, substituted aryl,heteroaryl, and substituted heteroaryl. In certain embodiments, each R²⁰and R²¹ is independently selected from hydrogen or phenyl, optionallysubstituted with one or more substituents selected from halo, CN, NO₂,OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.

[0248] In certain embodiments of a compound of Formula (Ic), wherein ris 1, R²⁰ and R²¹ together with the carbon atoms to which R²⁰ and R²¹are attached form a cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl or substituted cycloheteroalkanyl ring. In certainembodiments, wherein r is 1, R²⁰ and R²¹ together with the carbon atomto which they are attached form a cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl ring.

[0249] In certain embodiments of a compound of Formula (Ic), each R²⁰and R²¹ is independently selected from hydrogen, C₁₋₁₆ alkyl,substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.

[0250] In certain embodiments of a compound of Formulae (Ib) or (Ic),R²⁸ and R²⁹ are independently selected from hydrogen, alkanyl, aryl, andalkoxycarbonyl. In certain embodiments, R²⁸ and R²⁹ are independentlyselected from hydrogen, methyl, ethyl, propyl, butyl, phenyl,methoxycarbonyl, and ethoxycarbonyl. In certain embodiments, R²⁸ and R²⁹are both hydrogen.

[0251] In certain embodiments of a compound of Formulae (Ib) or (Ic),R³¹ is hydrogen or C₁₋₈ alkyl. In certain embodiments, R³¹ is hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0252] Synthesis of Certain Compounds

[0253] Embodiments of carbidopa prodrugs and/or derivatives thereof canbe prepared by methods well known in the art.

[0254] In certain embodiments the compounds can be prepared from readilyavailable starting materials using the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures) are given, other process conditions canalso be used unless otherwise stated. Optimum reaction conditions canvary with the particular reactants or solvent used, but such conditionscan be determined by one skilled in the art by routine optimizationprocedures.

[0255] Additionally, as will be apparent to those skilled in the art,conventional protecting groups can be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts, Protecting Groups in OrganicSynthesis ⁵ and references cited therein.

[0256] Furthermore, in certain embodiments the carbidopa prodrugs andderivatives thereof can contain one or more chiral centers. Accordingly,such compounds can be prepared or isolated as pure stereoisomers, i.e.,as individual enantiomers or diastereomers, or as stereoisomer-enrichedmixtures. All such stereoisomers (and enriched mixtures) are includedwithin the scope of the embodiments, unless otherwise indicated. Purestereoisomers (or enriched mixtures) can be prepared using, for example,optically active starting materials or stereoselective reagentswell-known in the art. Alternatively, racemic mixtures of such compoundscan be separated using, for example, chiral column chromatography,chiral resolving agents and the like.

[0257] In certain embodiments, carbidopa prodrugs and derivativesthereof can be prepared by methods well known in theart.^(5,11,12,16,23,25) The disclosures of these references are hereinincorporated by reference. Some of the preparative methods can be foundin U.S. Provisional Application No. 60/238,758³⁰ and InternationalPublication No. WO 02/28882³².

[0258] A compound of Formula (Ia) where, can be prepared as illustratedin Scheme 1 below. Reacting commercially available carbidopa with analcohol 11 in the presence of an appropriate coupling agent such asacetyl chloride affords an ester of compound of Formula 12 in which thehydrazine moiety is subsequently protected to provide a compound ofFormula 13.

[0259] Catechol moieties in 13 can be manipulated with differentprotecting groups to form mono- or di-substituted analogs as shown inScheme 2. Thus, treatment of a compound of Formula 13 with an acidhalide 14, a haloformate 15, an anhydride 16 or a halide 17 in thepresence of a base (e.g., TEA, Cs₂CO₃ etc.), in an appropriate solvent(e.g.; dichloromethane, acetone, etc) followed by removal of thehydrazine protecting group affords a mixture of mono-substitutedcompounds of Formulae 18 and 19 or a di-substituted compound of Formula20. For compounds wherein R⁴ and R⁵ are resistant to hydrolysis underbasic conditions (e.g. R⁴, R⁵=Me, Bn etc. or R⁴ and R⁵ are linked via—CR′R″C—), esters of Formulae 18, 19 and 20 can be converted to thecorresponding acids (R¹⁰=H, e.g. upon treatment with aq. LiOH).

[0260] Alternatively, compounds of Formulae 18-20 wherein R⁴ and R⁵ areacyl groups can be prepared directly from a compound of Formula 12 bytreatment with an acid halide 14 in the presence of an appropriate acidsuch as trifluoroacetic acid (TFA).

[0261] Illustrated in Scheme 3, the hydrazine moiety in carbidopa, 12,18, 19 and 20 can be elaborated by reacting with a nitrophenyl carbonateof Formula 21 under appropriate conditions to provide acyloxyalkylcarbamates of Formulae 22-26, respectively.

[0262] As shown in Scheme 5, compounds of Formulae (Ib) and (Ic) can beprepared by reacting a carboxylic acid 32 (obtained from treatment ofcarbidopa with (Boc)₂O in methanol) with an appropriate halide 33 or acompound of Formula 35, wherein D is OH, NH₂, NHR¹⁵, halide or otherleaving group, under appropriate alkylation or coupling conditions toprovide compounds of Formulae 36 and 38, respectively. Furthermore,treatment of compounds of Formulae 36 and 38 with electrophiles 14-17followed by removal of the protecting groups affords compounds ofFormulae 39 and 41, in which one or both of R⁴ and R⁵ are either acyl,alkoxycarbonyl, alkyl or substituted alkyl (Scheme 5). Directly removingthe protecting group (Boc) from compounds of Formulae 36 and 38 alsoaffords compounds of Formulae 39 and 41 in which R⁴ and R⁵ are bothhydrogen.

[0263] Therapeutic Uses of Certain Compounds

[0264] In accordance with certain embodiments, carbidopa prodrugs andderivatives thereof are decarboxylase enzyme inhibitors. Thus, incertain embodiments, a use of the carbidopa prodrugs and derivativesthereof is coadministration with another therapeutic agent or drug whichhas a tendency to be metabolized by one or more decarboxylase enzymesupon administration. Thus, the carbidopa prodrugs and derivativesthereof of the embodiments can be effective as protectants to inhibit orprevent decarboxylation of another coadministered therapeutic agent ordrug. The carbidopa prodrugs and derivatives thereof can be deliveredfrom the same dosage form as the therapeutic agent/drug that is subjectto decarboxylation, or from different dosage forms. The carbidopaprodrugs and derivatives thereof can be administered at the same timeas, prior to, or subsequent to, the administration of the therapeuticagent/drug subject to decarboxylation. The carbidopa prodrugs andderivatives can have particular utility in inhibiting thedecarboxylation of levodopa, and prodrugs and derivatives of levodopa,which are administered to humans suffering from Parkinson's disease.Further, in certain embodiments, the carbidopa prodrugs and derivativesthereof, together with levodopa or a levodopa prodrug or derivative, canbe administered to a patient, such as a human, to arrest, ameliorate,reduce the risk of acquiring, reduce the development of or at least oneof the clinical symptoms of, or reduce the risk of developing or atleast one of the clinical symptoms of, Parkinson's disease.

[0265] Certain embodiments of compounds and compositions of carbidopaprodrugs and derivatives thereof together with levodopa or a levodopaprodrug can be advantageously used in human medicine. As mentionedabove, in certain embodiments, the compounds and compositions can beuseful for the treatment of Parkinson's disease.

[0266] When used to treat the above disease, carbidopa prodrugs andderivatives thereof can be administered or applied in combination withlevodopa, and/or a levodopa prodrug that is subject to decarboxylation.Additionally, the therapeutic effectiveness of the above combinationscan be further enhanced by co-administration of another pharmaceuticallyactive agent (e.g., a catechol oxygen methyl transferase (COMT)inhibitor). Further, in certain embodiments, the carbidopa prodrugs andderivatives thereof, can be administered to a patient, such as a human,together with (i) L-dopa and/or an L-dopa prodrug, and (ii) apharmaceutically active agent (such as a catechol oxygen methyltransferase (COMT) inhibitor), can be administered to a patient, such asa human, to arrest, ameliorate, reduce the risk of acquiring, reduce thedevelopment of or at least one of the clinical symptoms of, or reducethe risk of developing or at least one of the clinical symptoms of,Parkinson's disease.

[0267] In certain embodiments, the carbidopa prodrugs and derivativesthereof can be administered orally. Certain carbidopa prodrugs andderivatives thereof can also be administered by any other convenientroute, for example, by infusion, absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa).

[0268] In certain embodiments, the compounds and/or compositions providecarbidopa and carbidopa prodrugs and derivatives thereof upon in vivoadministration to a patient. While not being bound by theory, thepromoiety or promoieties of the carbidopa prodrugs and derivativesthereof are currently believed to be cleaved either chemically and/orenzymatically. One or more enzymes present in the stomach, intestinallumen, intestinal tissue, blood, liver, brain or any other suitabletissue of a mammal can enzymatically cleave the promoiety or promoietiesof the compounds and/or compositions. The mechanism of cleavage is notimportant to the embodiments.

[0269] While not being bound by theory, the promoiety or promoieties ofcertain embodiments of the compounds and/or compositions can be designedto be cleaved after absorption by the gastrointestinal tract (e.g., inintestinal tissue, blood, liver or other suitable tissue of a mammal).In this situation, carbidopa prodrugs and derivatives thereof can havethe opportunity to be absorbed into the systemic circulation from thesmall and large intestines either by passive diffusion, active transportor by both passive and active processes. Certain compounds and/orcompositions of carbidopa prodrugs and derivatives thereof can beadministered as sustained release systems. In certain embodiments, thecompounds can be delivered by oral sustained release administration. Insome embodiments, the compounds can be administered twice per day and incertain embodiments, once per day.

[0270] Certain carbidopa prodrugs and derivatives thereof can be usefulin treating Parkinsonism by administration of one or more of thecarbidopa prodrugs and derivatives thereof together with levodopa or aprodrug of levodopa, in certain embodiments by the oral route, to amammalian subject in need of the treatment. In a human subject weighing70 kg, a carbidopa prodrug or derivative thereof can be administered ata dose ranging from 10 mg to 10 g per day, and in certain embodimentsranging from 100 mg to 1 g per day. The dose can be adjusted by oneskilled in the art based on several factors, e.g. the body weight and/orcondition of the subject treated, the dose of the levodopa, levodopaprodrug being administered, the severity of the Parkinson's disease, andthe incidence of side effects, the manner of administration and thejudgment of the prescribing physician.

[0271] Many compounds are also useful in treating hypertension (highblood pressure) by administration of one or more of the carbidopaprodrugs and derivatives thereof either alone or with anotherhypotensive agent such as clonidine, hydralazine, or guanethidine.Examples of hypotensive agents which can be coadministered with acarbidopa prodrug or derivative thereof are disclosed in U.S. Pat. Nos.4,055,645 and 4,156,734, the disclosures of which are incorporatedherein by reference. In certain embodiments, the hypotensive carbidopaprodrug or derivative thereof can be administered by the oral route to amammalian subject to be treated for hypertension. The same dosage rangesmentioned above for treating Parkinson's disease can be used foradministering the hypotensive carbidopa prodrugs and derivatives thereofin the treatment of hypertension.

[0272] For example, the dosage can be delivered in a composition by asingle administration, by multiple applications, by sustained release orby controlled sustained release. These latter two are discussed in moredetail herein.

[0273] Suitable dosage ranges for oral administration can be dependenton the potency of the parent carbidopa or carbidopa derivative drug, butgenerally range from 0.1 mg to 20 mg of a carbidopa prodrug orderivative thereof per kilogram of body weight. In the case of acarbidopa prodrug or derivative thereof that is metabolized in thepatient's body to release carbidopa, the amount of carbidopa releasedcan, in the case of adult patients, be in the range of 25-500 mg/day andthe dose of carbidopa prodrug or derivative thereof administered can beadjusted to provide an equivalent molar quantity of carbidopa. Othercarbidopa prodrugs and derivatives thereof can be more potent thancarbidopa itself and lower doses can be appropriate for both the potentderivatives and prodrugs of such potent derivatives. Dosage ranges canbe readily determined by methods known to those skilled in the art.

[0274] The carbidopa prodrugs and derivatives thereof can be assayed invitro and in vivo, for the desired therapeutic or prophylactic activityprior to use in humans. For example, in vitro assays can be used todetermine whether administration of a specific carbidopa prodrug orderivative thereof or a combination of such prodrugs and derivatives isappropriate for reducing decarboxylase activity. Carbidopa prodrugs andderivatives thereof can also be demonstrated to be effective and safeusing animal model systems.

[0275] In certain embodiments, a therapeutically effective dose of acarbidopa prodrug or derivative thereof can provide therapeutic benefitwithout causing substantial toxicity. Toxicity of carbidopa prodrugs andderivatives thereof can be determined using standard pharmaceuticalprocedures and can be readily ascertained by the skilled artisan. Thedose ratio between toxic and therapeutic effect is the therapeuticindex. Certain carbidopa prodrugs and derivatives thereof can exhibitparticularly high therapeutic indices in treating diseases anddisorders. The dosage of a carbidopa prodrug or derivative thereof canbe within a range of circulating concentrations that include aneffective dose with little or no toxicity.

[0276] Formulations of Certain Compounds

[0277] In some embodiments, the carbidopa prodrugs and derivativesthereof can be administered by oral routes. Such compositions can beprepared in a manner well known in the pharmaceutical art and compriseat least one carbidopa prodrug or derivative. The present compositionscan contain a therapeutically effective amount of one or more carbidopaprodrugs and derivatives thereof, in some embodiments, in purified form,together with levodopa, and/or a levodopa prodrug, and a suitable amountof a pharmaceutically acceptable vehicle, so as to provide the form forproper administration to a patient.

[0278] Certain embodiments also include compositions that contain, asthe active ingredient, one or more of the carbidopa prodrugs andderivatives thereof associated with pharmaceutically acceptableexcipients, carriers, diluents and/or adjuvants. In making thecompositions, the active ingredient can be mixed with an excipient,diluted by an excipient or enclosed within such a carrier which can bein the form of a capsule, sachet, paper or other container. When theexcipient serves as a diluent, it can be a solid, semi-solid, or liquidmaterial, which acts as a vehicle, carrier or medium for the activeingredient. Thus, the compositions can be in the form of tablets, pills,powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,solutions, and syrups containing, for example, up to 90% by weight ofthe active compound using, for example, soft and hard gelatin capsules.

[0279] In preparing a formulation, it can be necessary to mill theactive compound to provide the appropriate particle size prior tocombining with other ingredients. If the active compound issubstantially insoluble, it ordinarily is milled to a particle size ofless than 200 mesh. If the active compound is substantially watersoluble, the particle size is normally adjusted by milling to provide asubstantially uniform distribution in the formulation, e.g. ˜40 mesh.

[0280] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions can be formulated so as to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient by employing procedures known in the art.

[0281] The compositions can be formulated in unit dosage form, eachdosage containing from 1 mg to 2 g of the active ingredient. “Unitdosage forms” refers to physically discrete units suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient, diluent, carrier and/or adjuvant.

[0282] The active compound can be administered in a therapeuticallyeffective amount. It will be understood, however, that the amount of thecompound actually administered will be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compoundadministered, the age, weight, and response of the individual patient,the severity of the patient's symptoms, and the like.

[0283] For preparing solid compositions such as tablets, the principalactive ingredient can be mixed with a pharmaceutical excipient, diluent,carrier and/or adjuvant to form a solid preformulation compositioncontaining a homogeneous mixture of a carbidopa prodrug or derivative.When referring to these preformulation compositions as homogeneous, itis meant that the active ingredient is dispersed evenly throughout thecomposition so that the composition can be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.This solid preformulation is then subdivided into unit dosage forms ofthe type described above containing, for example, from 0.1 mg to 2 g ofthe therapeutically effective carbidopa prodrug or derivative.

[0284] The tablets or pills comprising a carbidopa prodrug or derivativethereof can be coated or otherwise compounded to provide a dosage formaffording the advantage of prolonged action. For example, the tablet orpill can comprise an inner dosage and an outer dosage component, thelatter being in the form of an envelope over the former. The twocomponents can be separated by an enteric layer which serves to resistdisintegration in the stomach and permit the inner component to passintact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings. Suchmaterials include a number of polymeric acids and mixtures of polymericacids with such materials as shellac, cetyl alcohol, and celluloseacetate.

[0285] The liquid forms in which the compositions comprising carbidopaprodrugs and derivatives thereof can be incorporated for administrationorally or by injection include aqueous solutions suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, aswell as elixirs and similar pharmaceutical vehicles.

[0286] Sustained Release Oral Dosage Forms

[0287] Certain carbidopa prodrugs and derivatives thereof can bepracticed with a number of different dosage forms, which can be adaptedto provide sustained release of the prodrug or derivative upon oraladministration.

[0288] In certain embodiment, the dosage form can comprise beads that ondissolution or diffusion release the prodrug or derivative over anextended period of hours, in some embodiments, over a period of at least6 hours, in some embodiments, over a period of at least 8 hours and inother embodiments, over a period of at least 12 hours. The prodrug- orderivative-releasing beads can have a central composition or corecomprising a prodrug or derivative and pharmaceutically acceptablevehicles, including an optional lubricant, antioxidant and buffer. Thebeads can be medical preparations with a diameter ranging from 1 mm to 2mm. Individual beads can comprise doses of the prodrug or derivative,for example, doses of up to 40 mg of prodrug or derivative. The beads,in certain embodiments, can be formed of non-cross-linked materials toenhance their discharge from the gastrointestinal tract. The beads canbe coated with a release rate-controlling polymer that gives atimed-release profile.

[0289] The timed-release beads can be manufactured into a tablet fortherapeutically effective prodrug or derivative administration. Thebeads can be made into matrix tablets by the direct compression of aplurality of beads coated with, for example, an acrylic resin andblended with excipients such as hydroxypropylmethyl cellulose. Themanufacture of beads has been disclosed in the art (Lu, Int. J. Pharm.,1994, 112, 117-124; Pharmaceutical Sciences by Remington, 14^(th) ed, pp1626-1628 (1970); Fincher, J. Pharm. Sci. 1968, 57, 1825-1835; and U.S.Pat. No. 4,083,949) as has the manufacture of tablets (PharmaceuticalSciences, by Remington, ₁₇ ^(th) Ed, Ch. 90, pp. 1603-1625 (1985).

[0290] In certain embodiments, an oral sustained release pump can beused (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201; Saudek et al., 1989, N. Engl. J. Med. 321:574).

[0291] In certain embodiments, polymeric materials can be used (see“Medical Applications of Controlled Release,” Langer and Wise (eds.),CRC Press, Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,”Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol.Chem. 23:61; see also Levy et al., 1985, Science 228: 190; During etal., 1989, Ann. Neurol. 25:351; Howard et al, 1989, J. Neurosurg.71:105). In certain embodiments, polymeric materials can be used fororal sustained release delivery. In certain embodiments, polymersinclude sodium carboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose, and in someembodiments, hydroxypropylmethylcellulose. Other cellulose ethers havebeen described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3)1-9). Factors affecting drug release are well known to the skilledartisan and have been described in the art (Bamba et al., Int. J.Pharm., 1979, 2, 307).

[0292] In certain embodiments, enteric-coated preparations can be usedfor oral sustained release administration. In certain embodiments,coating materials include polymers with a pH-dependent solubility (i.e.,pH-controlled release), polymers with a slow or pH-dependent rate ofswelling, dissolution or erosion (i.e., time-controlled release),polymers that can be degraded by enzymes (i.e., enzyme-controlledrelease) and polymers that form firm layers that can be destroyed by anincrease in pressure (i.e., pressure-controlled release).

[0293] In certain embodiments, drug-releasing lipid matrices can be usedfor oral sustained release administration. One example is when solidmicroparticles of the prodrug or derivative are coated with a thincontrolled release layer of a lipid (e.g., glyceryl behenate and/orglyceryl palmitostearate) as disclosed in Farah et al., U.S. Pat. No.6,375,987 and Joachim et al., U.S. Pat. No. 6,379,700. The lipid-coatedparticles can optionally be compressed to form a tablet. Anothercontrolled release lipid-based matrix material which is suitable forsustained release oral administration comprises polyglycolizedglycerides as disclosed in Roussin et al., U.S. Pat. No. 6,171,615.

[0294] In certain embodiments, prodrug- or derivative-releasing waxescan be used for oral sustained release administration. Examples ofsuitable sustained prodrug- or derivative-releasing waxes are disclosedin Cain et al., U.S. Pat. No. 3,402,240 (carnauba wax, candedilla wax,esparto wax and ouricury wax); Shtohryn et al. U.S. Pat. No. 4,820,523(hydrogenated vegetable oil, bees wax, carnauba wax, paraffin,candedilla, ozokerite and mixtures thereof); and Walters, U.S. Pat. No.4,421,736 (mixture of paraffin and castor wax).

[0295] In certain embodiments, a controlled-release system can be placedin proximity to the target of the carbidopa prodrug or derivative, thusrequiring only a fraction of the systemic dose (see, e.g., Goodson, in“Medical Applications of Controlled Release,” supra, vol. 2, pp. 115-138(1984)). Other controlled-release systems discussed in Langer, 1990,Science 249:1527-1533 can also be used.

[0296] In certain embodiments, the dosage form can comprise a carbidopaprodrug or derivative thereof coated on a polymer substrate. The polymercan be an erodible, or a nonerodible polymer. The coated substrate canbe folded onto itself to provide a bilayer polymer drug dosage form. Forexample, a carbidopa prodrug or derivative thereof can be coated onto apolymer such as a polypeptide, collagen, gelatin, polyvinyl alcohol,polyorthoester, polyacetyl, or a polyorthocarbonate and the coatedpolymer folded onto itself to provide a bilaminated dosage form. Inoperation, the bioerodible dosage form erodes at a controlled rate todispense the prodrug or derivative over a sustained release period.Representative biodegradable polymers comprise a polymer selected frombiodegradable poly(amides), poly(amino acids), poly(esters), poly(lacticacid), poly(glycolic acid), poly(carbohydrate), poly(orthoester),poly(orthocarbonate), poly(acetyl), poly(anhydrides), biodegradablepoly(dehydropyrans), and poly(dioxinones) which are known in the art(Rosoff, Controlled Release of Drugs, Chap. 2, pp. 53-95 (1989); and inU.S. Pat. Nos. 3,811,444; 3,962,414; 4,066,747, 4,070,347; 4,079,038;and 4,093,709).

[0297] In certain embodiments, the dosage form can comprise a carbidopaprodrug or derivative thereof loaded into a polymer that releases theprodrug or derivative by diffusion through a polymer, or by flux throughpores or by rupture of a polymer matrix. The drug delivery polymericdosage form can comprise a concentration ranging from 10 mg to 2500 mghomogeneously contained in or on a polymer. The dosage form can compriseat least one exposed surface at the beginning of dose delivery. Thenon-exposed surface, when present, can be coated with a pharmaceuticallyacceptable material impermeable to the passage of the prodrug orderivative. The dosage form can be manufactured by procedures known inthe art. An example of providing a dosage form comprises blending apharmaceutically acceptable carrier like polyethylene glycol, with aknown dose of prodrug or derivative at an elevated temperature, like 37°C., and adding it to a silastic medical grade elastomer with across-linking agent, for example, octanoate, followed by casting in amold. The step is repeated for each optional successive layer. Thesystem is allowed to set for 1 hour, to provide the dosage form.Representative polymers for manufacturing the dosage form comprise amember selected from olefin, and vinyl polymers, addition polymers,condensation polymers, carbohydrate polymers, and silicon polymers asrepresented by polyethylene, polypropylene, polyvinyl acetate,polymethylacrylate, polyisobutylmethacrylate, polyalginate, polyamideand polysilicon. The polymers and procedures for manufacturing them havebeen described in the art (Coleman et al., Polymers 1990, 31, 1187-1231;Roerdink et al., Drug Carrier Systems 1989, 9, 57-10.; Leong et al.,Adv. Drug Delivery Rev. 1987, 1, 199-233; Roff et al., Handbook ofCommon Polymers 1971, CRC Press; U.S. Pat. No. 3,992,518).

[0298] In certain embodiments, the dosage form can comprise a pluralityof tiny pills. The tiny time-released pills provide a number ofindividual doses for providing various time doses for achieving asustained-release prodrug or derivative delivery profile over anextended period of time up to 24 hours. The matrix can comprise ahydrophilic polymer selected from a polysaccharide, agar, agarose,natural gum, alkali alginate including sodium alginate, carrageenan,fucoidan, furcellaran, laminaran, hypnea, gum arabic, gum ghatti, gumkaraya, gum tragacanth, locust bean gum, pectin, amylopectin, gelatin,and a hydrophilic colloid. The hydrophilic matrix can comprise aplurality of 4 to 50 tiny pills, each tiny pill comprising a dosepopulation selected from, for example, 10 ng, 0.5 mg, 1 mg, 1.2 mg, 1.4mg, 1.6 mg, 5.0 mg, etc. The tiny pills comprise a releaserate-controlling wall of 0.001 up to 10 mm thickness to provide for thetimed release of prodrug or derivative. Representative wall formingmaterials include a triglyceryl ester selected from glyceryltristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryllaureate, glyceryl didecenoate and glyceryl tridenoate. Other wallforming materials comprise polyvinyl acetate, phthalate, methylcellulosephthalate and microporous olefins. Procedures for manufacturing tinypills are disclosed in U.S. Pat. Nos. 4,434,153; 4,721,613; 4,853,229;2,996,431; 3,139,383 and 4,752,470.

[0299] In certain embodiments, osmotic delivery systems can be used fororal sustained release administration (Verma et al., Drug Dev. Ind.Pharm., 2000, 26:695-708). In certain embodiments, OROS® systems made byAlza Corporation, Mountain View, Calif. can be used for oral sustainedrelease drug delivery (Theeuwes et al., U.S. Pat. No. 3,845,770;Theeuwes et al., U.S. Pat. No. 3,916,899). In certain embodiments, thedosage form can comprise an osmotic dosage form, which comprises asemipermeable wall that surrounds a therapeutic composition comprisingthe carbidopa prodrug or derivative. In use within a patient, theosmotic dosage form comprising a homogenous composition imbibes fluidthrough the semipermeable wall into the dosage form in response to theconcentration gradient across the semipermeable wall. The therapeuticcomposition in the dosage form develops osmotic energy that causes thetherapeutic composition to be administered through an exit from thedosage form over a prolonged period of time up to 24 hours (or even insome cases up to 30 hours) to provide controlled and sustained prodrugor derivative release. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations.

[0300] In certain embodiments, the dosage form can comprise anotherosmotic dosage form comprising a wall surrounding a compartment, thewall comprising a semipermeable polymeric composition permeable to thepassage of fluid and substantially impermeable to the passage of thecarbidopa prodrug or derivative thereof present in the compartment, aprodrug- or derivative-containing layer composition in the compartment,a hydrogel push layer composition in the compartment comprising anosmotic formulation for imbibing and absorbing fluid for expanding insize for pushing the prodrug or derivative composition layer from thedosage form, and at least one passageway in the wall for releasing theprodrug or derivative composition. The method delivers the prodrug orderivative by imbibing fluid through the semipermeable wall at a fluidimbibing rate determined by the permeability of the semipermeable walland the osmotic pressure across the semipermeable wall causing the pushlayer to expand, thereby delivering the prodrug or derivative from thedosage form through the exit passageway to a patient over a prolongedperiod of time (up to 24 or even 30 hours). The hydrogel layercomposition can comprise 10 mg to 1000 mg of a hydrogel such as a memberselected from a polyalkylene oxide of 1,000,000 to 8,000,000weight-average molecular weight, which are selected from a polyethyleneoxide of 1,000,000 weight-average molecular weight, a polyethylene oxideof 2,000,000 weight-average molecular weight, a polyethylene oxide of4,000,000 weight-average molecular weight, a polyethylene oxide of5,000,000 weight-average molecular weight, a polyethylene oxide of7,000,000 weight-average molecular weight and a polypropylene oxide ofthe 1,000,000 to 8,000,000 weight-average molecular weight; or 10 mg to1000 mg of an alkali carboxymethylcellulose of 10,000 to 6,000,000weight average molecular weight, such as sodium carboxymethylcelluloseor potassium carboxymethylcellulose. The hydrogel expansion layer cancomprise 0.0 mg to 350 mg, such as 0.1 mg to 250 mg, of ahydroxyalkylcellulose of 7,500 to 4,500,00 weight-average molecularweight (e.g., hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxybutylcellulose orhydroxypentylcellulose); 1 mg to 50 mg of an osmagent selected fromsodium chloride, potassium chloride, potassium acid phosphate, tartaricacid, citric acid, raffinose, magnesium sulfate, magnesium chloride,urea, inositol, sucrose, glucose and sorbitol; 0 to 5 mg of a colorant,such as ferric oxide; 0 mg to 30 mg, such as 0.1 mg to 30 mg, of ahydroxypropylalkylcellulose of 9,000 to 225,000 average-number molecularweight, selected from hydroxypropylethylcellulose,hydroxypropypentylcellulose, hydroxypropylmethylcellulose, andhydropropylbutylcellulose; 0.0 to 1.5 mg of an antioxidant selected fromascorbic acid, butylated hydroxyanisole, butylatedhydroxyquinone,butylhydroxyanisol, hydroxycoumarin, butylated hydroxytoluene, cephalm,ethyl gallate, propyl gallate, octyl gallate, lauryl gallate,propyl-hydroxybenzoate, trihydroxybutylrophenone, dimethylphenol,dibutylphenol, vitamin E, lecithin and ethanolamine; and 0.0 mg to 7 mgof a lubricant selected from calcium stearate, magnesium stearate, zincstearate, magnesium oleate, calcium palmitate, sodium suberate,potassium laureate, salts of fatty acids, salts of alicyclic acids,salts of aromatic acids, stearic acid, oleic acid, palmitic acid, amixture of a salt of a fatty, alicyclic or aromatic acid, and a fatty,alicyclic, or aromatic acid.

[0301] In the osmotic dosage forms, the semipermeable wall can comprisea composition that is permeable to the passage of fluid and impermeableto the passage of the carbidopa prodrug or derivative. The wall can benontoxic and can comprise a polymer selected from a cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate and cellulose triacetate. The wall can comprise 75 wt %(weight percent) to 100 wt % of the cellulosic wall-forming polymer; or,the wall can comprise additionally 0.01 wt % to 80 wt % of polyethyleneglycol, or 1 wt % to 25 wt % of a cellulose ether selected fromhydroxypropylcellulose or a hydroxypropylalkycellulose such ashydroxypropylmethylcellulose. The total weight percent of all componentscomprising the wall is equal to 100 wt %. The internal compartment cancomprise the prodrug- or derivative-containing composition alone or inlayered position with an expandable hydrogel composition. The expandablehydrogel composition in the compartment increases in dimension byimbibing the fluid through the semipermeable wall, causing the hydrogelto expand and occupy space in the compartment, whereby the prodrug orderivative composition is pushed from the dosage form. The therapeuticlayer and the expandable layer act together during the operation of thedosage form for the release of prodrug or derivative to a patient overtime. The dosage form can comprise a passageway in the wall thatconnects the exterior of the dosage form with the internal compartment.The osmotic powered dosage form provided by certain embodiments deliversthe carbidopa prodrug or derivative thereof from the dosage form to thepatient at a zero order rate of release over a period of up to abouthours.

[0302] The expression “passageway” as used herein comprises means andmethods suitable for the metered release of the carbidopa prodrug orderivative thereof from the compartment of the dosage form. The exitmeans comprises at least one passageway, including orifice, bore,aperture, pore, porous element, hollow fiber, capillary tube, channel,porous overlay, or porous element that provides for the osmoticcontrolled release of prodrug or derivative. The passageway includes amaterial that erodes or is leached from the wall in a fluid environmentof use to produce at least one controlled-release dimensionedpassageway. Representative materials suitable for forming a passageway,or a multiplicity of passageways comprise a leachable poly(glycolic)acid or poly(lactic) acid polymer in the wall, a gelatinous filament,poly(vinyl alcohol), leach-able polysaccharides, salts, and oxides. Apore passageway, or more than one pore passageway, can be formed byleaching a leachable compound, such as sorbitol, from the wall. Thepassageway possesses controlled-release dimensions, such as round,triangular, square and elliptical, for the metered release of prodrug orderivative from the dosage form. The dosage form can be constructed withone or more passageways in spaced apart relationship on a single surfaceor on more than one surface of the wall. The expression “fluidenvironment” denotes an aqueous or biological fluid as in a humanpatient, including the gastrointestinal tract. Passageways and equipmentfor forming passageways are disclosed in U.S. Pat. Nos. 3,845,770;3,916,899; 4,063,064; 4,088,864 and 4,816,263. Passageways formed byleaching are disclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987 .

[0303] Regardless of the specific form of sustained release oral dosageform used, the carbidopa prodrug or derivative thereof can be releasedfrom the dosage form over a period of at least 6 hours, in someembodiments, over a period of at least 8 hours, and in some embodiments,over a period of at least 12 hours. Further, the dosage form can releasefrom 0 to 20% of the carbidopa prodrug or derivative thereof in 0 to 2hours, from 20 to 50% of the prodrug or derivative thereof in 2 to 12hours, from 50 to 85% of the prodrug or derivative thereof in 3 to 20hours and greater than 75% of the prodrug or derivative thereof in 5 to18 hours.

[0304] In certain embodiments, the dosage forms can be administeredtwice per day, and in some embodiments, once per day.

EXAMPLES

[0305] Certain embodiments can be further defined by reference to thefollowing examples, which describe in detail preparation of compoundsand compositions comprising carbidopa prodrugs and derivatives thereofand assays for using compounds and compositions comprising carbidopaprodrugs and derivatives thereof. It will be apparent to those skilledin the art that many modifications, both to materials and methods, canbe practiced without departing from the embodiments.

[0306] The following synthetic and biological examples are offered toillustrate certain embodiments and are not to be construed in any way aslimiting the scope. Unless otherwise stated, all temperatures are indegrees Celsius. In the examples below, the following abbreviations havethe following meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning.

[0307] Atm=atmosphere

[0308] Boc=tert-butyloxycarbonyl

[0309] Cbz=carbobenzyloxy

[0310] CPM=counts per minute

[0311] DCC=dicyclohexylcarbodiimide

[0312] DMAP=4-N,N-dimethylaminopyridine

[0313] DMEM=Dulbecco's minimum eagle medium

[0314] DMF=N,N-dimethylformamide

[0315] DMSO=dimethylsulfoxide

[0316] Fmoc=9-fluorenylmethyloxycarbonyl

[0317] g=gram

[0318] hr=hour

[0319] HBSS=Hank's buffered saline solution

[0320] L=liter

[0321] LC/MS=liquid chromatography/mass spectroscopy

[0322] M=molar

[0323] min=minute

[0324] mL=milliliter

[0325] mmol=millimoles

[0326] NHS=N-hydroxysuccinimide

[0327] PBS=phosphate buffered saline

[0328] THF=tetrahydrofuran

[0329] TFA=trifluoroacetic acid

[0330] TMS=trimethylsilyl

[0331] μL=microliter

[0332] μM=micromolar

[0333] v/v=volume to volume

Example 13-(3,4-Bis-ethoxycarbonyloxy-phenyl)-2-hydrazino-2-methyl-propionic AcidAcetoxymethyl Ester (101)

[0334] Step A:2-(N′-tert-Butoxycarbonyl-hydrazino)-3-(3,4-dihydroxy-phenyl)-2-methyl-propionicAcid (102)

[0335] To a mixture of carbidopa (5 g, 20 mmol), triethylamine (3 mL, 21mmol) in methanol, was added Boc anhydride (4.7 g, 21 mmol) at 0° C. Thereaction mixture was stirred at room temperature for 16 h undernitrogen. After removing the solvent under reduced pressure, the productwas partitioned between ethyl acetate and 10% citric acid. The organiclayer was separated, dried over MgSO₄ and concentrated to give 6.2 g(95%) of the title compound. ¹H NMR (CD₃OD, 400 MHz): 1.28 (s, 3H), 1.46(s, 9H), 2.83 (dd, 2H), 6.60 (m, 3H). MS (ESI) m/z 349.21 (M+Na⁺).

[0336] Step B:2-(N′-tert-Butoxycarbonyl-hydrazino)-3-(3,4-Dihydroxy-phenyl)-2-methyl-propionicAcid Acetoxymethyl Ester (103)

[0337] To a suspension of compound 102 (170 mg, 0.5 mmol) and cesiumbicarbonate (99 mg, 0.5 mmol) in acetone was added bromomethyl acetate(170 mg, 0.5 mmol) and the mixture stirred at 44° C. temperature for 16h. After removing the solvent under reduced pressure, the residue waspartitioned between ethyl acetate and 10% citric acid. The organic layerwas separated, dried over MgSO₄ and concentrated to afford the crudeproduct, which was used in the next reaction without furtherpurification.

[0338] Step C:3-(3,4-Bis-ethoxycarbonyloxy-phenyl)-2-hydrazino-2-methyl-propionic AcidAcetoxymethyl Ester (101)

[0339] To an ice cold reaction mixture containing compound 103 (0.358 g,0.9 mmol) and TEA (0.224 mL, 1.8 mmol) in dichloromethane (5 mL) wasadded ethyl chloroformate (0.18 mL, 1.8 mmol). The mixture was stirredat 0° C. for 30 min and then at room temperature for 1 h. After removalof solvent, 10% citric acid was added and the organic phase wasseparated and dried over MgSO₄. After removing the solvent under reducedpressure, the resulting residue was treated with 50% trifluoroaceticacid in dichloromethane at room temperature for 30 min. After removingthe solvent under reduced pressure, the resulting residue was purifiedby reverse phase preparative HPLC to afford 208 mg of the titlecompound. ¹H NMR (CD₃OD, 400 MHz): 1.35 (t, 6H), 1.45 (s, 3H), 3.08 (dd,2H), 3.80 (s, 3H), 4.28 (q, 4H), 5.83 (dd, 2H), 7.12-7.24 (m, 3H). MS(ESI) m/z 443.28 (M+H⁺).

Example 2 3-(3,4-Dihydroxyphenyl)-2-hydrazino-2-methyl-propionic AcidAcetoxymethyl Ester (104)

[0340] Crude 103 was treated in a flask with 50% trifluoroacetic acid indichloromethane at room temperature for 30 min. After removing thesolvent under reduced pressure, the resulting residue was purified byreverse phase preparative HPLC to afford 57 mg of the title compound. ¹HNMR (CD₃OD, 400 MHz): 1.37 (s, 3H), 1.98 (s, 3H), 2.82 (dd, 2H), 5.02(s, 2H), 6.50 (m, 3H). MS (ESI) m/z 299.24 (M+H⁺).

Example 33-(3,4-Bis-ethoxycarbonyloxy-phenyl)-2-hydrazino-2-methyl-propionic Acid2,2-dimethyl-propionyloxymethyl Ester (105)

[0341] Following the procedure for preparation of compound 101, andsubstituting bromomethyl acetate with iodomethyl pivalate, provided thetitle compound. ¹H NMR (CD₃OD, 400 MHz): 1.24 (s, 9H), 1.34 (t, 6H),1.44 (s, 3H), 3.08 (dd, 2H), 4.29 (q, 4H), 5.88 (dd, 2H), 7.19-7.25 (m,3H). MS (ESI) m/z 485.32 (M+H⁺)

Example 43-(3,4-Bis-ethoxycarbonyloxy-phenyl)-2-hydrazino-2-methyl-propionic AcidMethyl Ester (106)

[0342] Step A: Methyl3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methyl-propionate (107)

[0343] To a solution of carbidopa (226 mg, 1 mmol) in anhydrous methanol(20 mL), was added acetyl chloride (1 mL) at 0° C. The mixture wasstirred at 65° C. in a pressure vessel for 4 h. Removal of solventyielded 270 mg (99%) of the title compound as its hydrochloride salt. ¹HNMR (CD₃OD, 400 MHz): 1.46 (s, 3H), 2.86 (dd, 2H), 3.78 (s, 3H), 6.45(dd, J=8 Hz, J=2 Hz), 6.56 (d, J=2.4 Hz), 6.69 (d, J=8.4 Hz). MS (ESI)m/z 241.15 (M+H⁺).

[0344] Step B:2-(N′-tert-Butoxycarbonyl-hydrazino)-3-(3,4-dihydroxy-phenyl)-2-methyl-propionicAcid Methyl Ester (108)

[0345] Following the procedure in Example 1 Step A, and substitutingcarbidopa with carbidopa methyl ester 107, provided the title compound.¹NMR (CD₃OD, 400 MHz): 1.22 (s, 3H), 1.42 (s, 9H), 2.80 (dd, 2H), 3.70(s, 3H), 6.60 (m, 3H). MS (ESI) m/z 341.44 (M+H⁺).

[0346] Step C:3-(3,4-Bis-ethoxycarbonyloxy-phenyl)-2-hydrazino-2-methyl-propionic AcidMethyl Ester (106)

[0347] Following the procedure in Example 1 Step C, and substituting 103with 108, provided the title compound. ¹H NMR (CD₃OD, 400 MHz): 1.36 (t,6H), 1.45 (s, 3H), 3.10 (dd, 2H), 3.80 (s, 3H), 4.30 (q, 4H), 7.15-7.28(m, 3H). MS (ESI) m/z 385.42 (M+H⁺).

Example 53-[3,4-Bis-(2,2-dimethyl-propionyloxy)-phenyl]-2-hydrazino-2-methyl-propionicAcid Methyl Ester (109)

[0348] Following the procedure in Example 4 Step C, and substitutingethyl chloroformate with pivalic anhydride, provided the title compound.¹H NMR (CD₃OD, 400 MHz): 1.37 (s, 18H), 1.46 (s, 3H), 3.11 (dd, 2H),3.80 (s, 3H), 7.06-7.19 (m, 3H). MS (ESI) m/z 409.39 (M+H⁺).

Example 63-(3,4-Bis-ethoxycarbonyloxy-phenyl)-2-hydrazino-2-methyl-propionic Acid(110)

[0349] Following the procedure for preparation of 106, and substitutingethyl chloroformate and 108 with diethyl pyrocarbonate and 102,respectively, provided the title compound. ¹H NMR (CD₃OD, 400 MHz): 1.18(t, 6H), 1.36 (s, 3H), 3.01 (dd, 2H), 3.80 (s, 3H), 4.17 (q, 4H),7.08-7.17 (m, 3H). MS (ESI) m/z 371.24 (M+H⁺).

Example 73-[3,4-Bis-(2,2-dimethyl-propionyloxy)-phenyl]-2-hydrazino-2-methyl-propionicAcid (111)

[0350] Following the procedure for preparation of 106, and substitutingethyl chloroformate and 108 with pivalic anhydride and 102,respectively, provided the title compound. ¹H NMR (CD₃OD, 400 MHz): 1.34(s, 18H), 1.46 (s, 3H), 3.11 (dd, 2H), 7.06-7.19 (m, 3H). MS (ESI) m/z395.36 (M+H⁺).

Example 8 3-(3,4-Dihydroxy-phenyl)-2-hydrazino-2-methyl-propionic Acid2,2-dimethyl-propionyloxymethyl Ester (112)

[0351] Following the procedures described in Examples 1 and 2, andsubstituting bromomethyl acetate with iodomethyl pivalate, provided thetitle compound. ¹H NMR (CD₃OD, 400 MHz): 1.24 (s, 9H), 1.44 (s, 3H),2.90 (dd, 2H), 5.86 (s, 2H), 6.58 (m, 3H). MS (ESI) m/z 341.28 (M+H⁺).

Example 92-Hydrazino-3-[3-hydroxy-4-(3-oxo-1,3-dihydro-isobenzofuran-1-yloxy)-phenyl]-2-methyl-propionicAcid Methyl Ester (113) and2-Hydrazino-3-[4-hydroxy-3-(3-oxo-1,3-dihydro-isobenzofuran-1-yloxy)-phenyl]-2-methyl-propionicAcid Methyl Ester (114)

[0352] A mixture of compound 108 (380 mg, 1.1 mmol), bromophthalide (213mg, 1 mmol) and CsHCO₃ (325 mg, 1 mmol) in acetone was stirred at roomtemperature for 16 h. After removing the solvent under reduced pressure,the residue was partitioned between 10% citric acid and ethyl acetate.The organic phase was separated and dried over MgSO₄. After removing thesolvent under reduced pressure, the resulting residue was treated with50% trifluoroacetic acid in dichloromethane at room temperature for 30min. After removing the solvent, the resulting residue was purified byreverse phase preparative HPLC to afford two separated stereoisomers 113(123 mg) and 114 (120 mg), respectively. Compound 113: ¹H NMR (CD₃OD,400 MHz): 1.43 (s, 3H), 2.98 (dd, 2H), 3.80 (s, 3H), 6.62-7.20 (m, 4H),7.66-7.95 (m, 4H). MS (ESI) m/z 373.25 (M+H⁺) and Compound 114:¹H NMR(CD₃OD, 400 MHz): 1.44 (s, 3H), 2.99 (dd, 2H), 3.84 (s, 3H), 6.80-7.18(m, 4H), 7.69-7.93 (m, 4H). MS (ESI) m/z 373.25 (M+H⁺).

Example 103-[4-(2,2-Dimethyl-propionyloxymethoxy)-3-hydroxy-phenyl]-2-hydrazino-2-methyl-propionicAcid Methyl Ester (115) and3-[3-(2,2-Dimethyl-propionyloxymethoxy)-3-hydroxy-phenyl]-2-hydrazino-2-methyl-propionicAcid Methyl Ester (116)

[0353] Following the procedure for preparation of compounds 113 and 114,and substituting bromophthalide with iodomethyl pivalate, provided thetitle compounds 115 and 116, respectively. Compound 115: ¹H NMR (CD₃OD,400 MHz): 1.18 (s, 9H), 1.45 (s, 3H), 2.98 (dd, 2H), 3.78 (s, 3H), 5.74(s, 2H), 6.58-6.98 (m, 3H). MS (ESI) m/z 355.30 (M+H⁺) and Compound 116:¹H NMR (CD₃OD, 400 MHz): 1.20 (s, 9H), 1.46 (s, 3H), 2.98 (dd, 2H), 3.78(s, 3H), 5.75 (dd, 2H), 6.68-6.89 (m, 3H). MS (ESI) m/z 355.38 (M+H⁺).

Example 113-(4-Benzyloxy-3-hydroxy-phenyl)-2-hydrazino-2-methyl-propionic AcidMethyl Ester (117) and3-(3-Benzyloxy-3-hydroxy-phenyl)-2-hydrazino-2-methyl-propionic AcidMethyl Ester (118)

[0354] Following the procedure for preparation of compounds 113 and 114,and substituting bromophthalide with benzyl bromide, provided the titlecompounds 117 and 118, respectively. Compound 117: ¹H NMR (CD₃OD, 400MHz): 1.38 (s, 3H), 2.90 (dd, 2H), 3.65 (s, 3H), 5.15 (s, 2H), 6.59-6.78(m, 3H), 7.27-7.44 (m, 4H). MS (ESI) m/z 331.30 (M+H⁺) and compound 118:¹H NMR (CD₃OD, 400 MHz): 1.42 (s, 3H), 2.92 (dd, 2H), 3.65 (s, 3H), 5.15(s, 2H), 6.45-6.92 (m, 3H), 7.24-7.44 (m, 4H). MS (ESI) m/z 331.29(M+H⁺).

Example 123-[3,4-Bis-(3-oxo-1,3-dihydro-isobenzofuran-1-yloxy)-phenyl]-2-hydrazino-2-methyl-propionicAcid Methyl Ester (119)

[0355] A mixture of compound 108 (170 mg, 0.5 mmol), bromophthalide (213mg, 1 mmol) and Cs₂CO₃ (325 mg, 1 mmol) in acetone was stirred at 40° C.for 16 h. After removing the solvent under reduced pressure, the residuewas partitioned between 10% citric acid and ethyl acetate. The organicphase was separated and dried over MgSO₄, and concentrated to dryness.The resulting residue was treated with 50% trifluoroacetic acid indichloromethane at room temperature for 30 min. Removal of the solventand purification of the resulting residue by reverse phase HPLC afford81 mg of 119 as a mixture of diastereomers. ¹H NMR (CD₃OD, 400 MHz):1.50 (3H), 3.10 (2H), 3.84 (3H), 6.86-7.18 (m, 3H), 7.22-7.44 (m, 2H),7.61-7.95 (m, 8H). MS (ESI) m/z 505.26.

Example 13 3-(3,4-Dimethoxy-phenyl)-2-hydrazino-2-methyl-propionic AcidMethyl Ester (120)

[0356] Following the procedure for preparation of compound 119, andsubstituting bromophthalide with iodomethane, provided the titlecompound 120. ¹H NMR (CD₃OD, 400 MHz): 1.44 (s, 3H), 3.00 (dd, 2H), 3.80(2 s, 6H), 4.77 (s, 3H), 6.71-6.86 (m, 3H). MS (ESI) m/z 269.33 (M+H⁺).

Example 14

[0357] 3-(3,4-Dimethoxy-phenyl)-2-hydrazino-2-methyl-propionic Acid(121)

[0358] Following the procedure for preparation of compound 119, andtreatment of the resulting 120 with 0.33M of LiOH in H₂O/MeOH/THF beforeBoc removal by TFA, provided the title compound 121. ¹H NMR (CD₃OD, 400MHz): 1.49 (s, 3H), 3.05 (dd, 2H), 3.80 (2 s, 6H), 6.77-6.92 (m, 3H). MS(ESI) m/z 255.25 (M+H⁺).

Example 15

[0359] 3-(3,4-Dihydroxy-phenyl)-2-hydrazino-2-methyl-propionic Acid3-oxo-1,3-dihydro-isobenzofuran-1-yl Ester (122)

[0360] Following the procedure for preparation of compound 104, andsubstituting bromomethyl acetate with bromophthalide, provided the titlecompound 122 as a mixture of diastereomers. MS (ESI) m/z 359.03 (M+H⁺).

Example 163-(3-Ethoxycarbonyloxy-4-hydroxy-phenyl)-2-hydrazino-2-methyl-propionicAcid Methyl Ester (123) and3-(4-Ethoxycarbonyloxy-3-hydroxy-phenyl)-2-hydrazino-2-methyl-propionicAcid Methyl Ester (124)

[0361] To an ice cold reaction mixture containing compound 108 (0.17 g,0.5 mmol) and TEA (0.07 mL, 0.5 mmol) in dichloromethane (5 mL) wasadded ethyl chloroformate (0.025 mL, 0.5 mmol). The resulting mixturewas stirred at 0° C. for 30 min and then at room temperature for 1.After concentration, the residue was partitioned with 10% citric acidand ethyl acetate. The organic phase was separated and dried over MgSO₄.After removing the solvent under reduced pressure, the resulting residuewas treated with 50% trifluoroacetic acid in dichloromethane at roomtemperature for 30 min. Removal of the solvent and purification byreverse phase preparative HPLC afford 73 mg of a 1:1 mixture of thetitle compounds 123 and 124. ¹H NMR (CD₃OD, 400 MHz): 1.35 (q, 3H), 1.46(d, 3H), 2.98 (dd, 2H), 3.80 (d, 3H), 4.28 (q, 4H), 6.60-6.98 (m, 3H).MS (ESI) m/z 313.25 (M+H⁺).

Example 17 2,6-Dimethyl-benzoic Acid4-(2-carboxy-2-hydrazino-propyl)-2-hydroxy-phenyl Ester (125) and2,6-Dimethyl-benzoic Acid5-(2-carboxy-2-hydrazino-propyl)-2-hydroxy-phenyl Ester (126)

[0362] To a solution of carbidopa (732 mg, 3 mmol) in trifluoroaceticacid (10 mL), was slowly added 2,6-dimethyl-benzoyl chloride (504 mg, 3mmol) at 0° C. and the mixture stirred at room temperature for 1 h. Thereaction mixture was concentrated under reduced pressure. The oilyresidue was dissolved in acetonitrile/H₂O and purified by reverse phasepreparative HPLC to afford 196 mg of compound 125 [¹H NMR (CD₃OD, 400MHz) 1.49 (s, 3H), 2.45 (d, 6H), 3.10 (dd, 2H), 6.82-7.25 (m, 6H). MS(ESI) m/z 359.23 (M+H⁺)] and 161 mg of compound 126 [¹H NMR (CD₃OD, 400MHz): 1.45 (s, 3H), 2.42 (d, 6H), 3.15 (dd, 2H), 6.74-7.27 (m, 6H). MS(ESI m/z 359.23 (M+H⁺)].

Example 18 2,6-Dimethyl-benzoic Acid4-(2-hydrazino-2-methoxycarbonyl-propyl)-2-hydroxy-phenyl Ester (127)and 2,6-Dimethyl-benzoic Acid5-(2-hydrazino-2-methoxycarbonyl-propyl)-2-hydroxy-phenyl Ester (128)

[0363] Following the procedure for preparation of compounds 125 and 126,and substituting carbidopa with carbidopa methyl ester, provided thetitle compounds 127 [¹H NMR (CD₃OD, 400 MHz): 1.42 (s, 3H), 2.43 (d,6H), 3.10 (dd, 2H), 3.78 (s, 3H), 6.82-7.30 (m, 6H). MS (ESI) m/z 373.08(M+H⁺)] and 128 [¹H NMR (CD₃OD, 400 MHz): 1.43 (s, 3H), 2.42 (d, 6H),3.02 (dd, 2H), 3.80 (s, 3H), 6.65-7.22 (m, 6H). MS (ESI) m/z 373.08(M+H⁺)].

Example 19 2-Methyl-benzoic Acid4-(2-hydrazino-2-carbonyl-propyl)-2-hydroxy-phenyl Ester (129) and2-Methyl-benzoic Acid 5-(2-hydrazino-2-carbonyl-propyl)-2-hydroxy-phenylEster (130)

[0364] Following the procedure for preparation of compounds 125 and 126,and substituting 2,6-dimethyl-benzoyl chloride with 2-methyl-benzoylchloride, provided the title compounds 129 and 130 as a mixture of twoinseparable regioisomers. ¹H NMR (CD₃OD, 400 MHz): 1.10 (d, 3H), 2.21(d, 3H), 2.64 (dd, 2H), 6.36-7.75 (m, 7H). MS (ESI) m/z 343.23 (M−H⁺).

Example 20 2-Methyl-benzoic Acid4-{2-carboxy-2-[N′-(2,2-dimethyl-propionyloxy-methoxycarbonyl)-hydrazino]-propyl}-2-hydroxy-phenylEster (131) and 2-Methyl-benzoic Acid5-{2-carboxy-2-[N′-(2,2-dimethyl-propionyloxy-methoxycarbonyl)-hydrazino]-propyl}-2-hydroxy-phenylEster (132)

[0365] To a mixture of compounds 129 and 130 (194 mg, 0.34 mmol) indimethylformamide (5 mL) was added α-pivaloxymethyl-p-nitrophenylcarbonate (0.1 g, 0.34 mmol) and triethylamine (0.142 mL, 1.02 mmol) atroom temperature. After stirring for 30 min, the mixture was partitionedbetween ethyl acetate and 10% citric acid. The organic layer wasseparated, dried (MgSO₄) and concentrated to dryness. The resultingresidue was purified by reverse phase preparative HPLC to afford 113 mgof the title compounds as a mixture of regioisomers. ¹H NMR (CD₃OD, 400MHz): 1.18 (d, 9H), 1.21 (d, 3H), 2.60 (d, 3H), 2.90 (dd, 2H), 5.70 (d,2H), 6.73-8.15 (m, 7H). MS (ESI) m/z 503.20 (M+H⁺).

Example 21 3-(3,4-Dihydroxy-phenyl)-2-hydrazino-2-methyl-propionic Acid2-phenoxy-ethyl Ester (133)

[0366] Following the procedure described in Example 4 Step A forpreparation of compound 107, and substituting methanol with2-phenoxy-ethanol, provided the title compound. ¹H NMR (CD₃OD, 400 MHz):1.65 (s, 3H), 3.10 (dd, 2H), 4.40 (t, 2H), 4.70 (t, 2H), 6.60-6.52 (m,8H). MS (ESI) m/z 347.27 (M+H⁺).

Example 22 Ethyl3-(3,4-dihydroxyphenyl)-2-[N′-(2,2-dimethyl-propionyloxy-methoxycarbonyl)-hydrazino]-2-methyl-propionate(134)

[0367] Step A: Ethyl3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methyl-propionate (135)

[0368] Following the procedure for preparation of compound 107, andsubstituting methanol with ethanol, provided the title compound, whichwas used in the next reaction without further purification.

[0369] Step B: Ethyl3-(3,4-dihydroxyphenyl)-2-[N′-(2,2-dimethyl-propionyloxy-methoxycarbonyl)-hydrazino]-2-methyl-propionate(134)

[0370] To a pressure vessel containing compound 135 (1 g, 4 mmol) andtriethylamine (11.2 mL, 80 mmol), chloroform (50 mL), and acetonitrile(20 mL) was added N,O-bis(trimethylsilyl)acetamide (3.3 mL, 13.2 mmol)and the resulting mixture was stirred until a clear solution is formed.A solution containing α-pivaloxymethyl-p-nitrophenyl carbonate (0.63 g,4 mmol) in chloroform (10 mL) was then added and stirred at 55° C. for48 h. After concentration, the residue was partitioned between 10%citric acid and ethyl acetate. The organic layer was separated and theaqueous layer was further extracted with ethyl acetate (3×20 mL). Thecombined organic extracts were dried over MgSO₄ and then concentrated invacuo. Chromatography of the resulting residue on silica gel, elutingwith hexane:ethyl acetate (7:3) to remove nitrophenol, then eluting withethyl acetate/methanol/acetic acid (100:10:0.5) afforded the crudeproduct. Further purification by reverse preparative HPLC gave 60 mg ofthe title compound. ¹H NMR (CDCl₃, 400 MHz): 1.22 (s, 9H), 1.29 (t, 3H),1.38 (s, 3H), 2.82 (dd, 2H), 5.75 (dd, 2H), 6.53 (dd, 1H), 6.71 (m, 2H).MS (ESI) m/z 413.37 (M+H⁺).

Example 233-(3,4-dihydroxyphenyl)-2-[N′-(2,2-dimethyl-propionyloxy-methoxycarbonyl)-hydrazino]-2-methyl-propionicAcid (136)

[0371] To a pressure vessel containing carbidopa (2.26 g, 10 mmol),triethylamine (37 mL, 50 mmol), chloroform (150 mL), and acetonitrile(50 mL) was added trimethylchlorosilane (6.3 mL, 50 mmol) and themixture stirred until the carbidopa fully dissolved. A solutioncontaining α-pivaloxymethyl-p-nitrophenyl carbonate (2.0 g, 7 mmol) inchloroform (20 mL) was added and stirred at 65° C. for 24 h. Afterremoving the solvent, the mixture was partitioned with 10% citric acidand ethyl acetate. The organic layer was separated and the aqueous layerwas further extracted with ethyl acetate (3×60 mL). The combined organicextracts were dried over MgSO₄ and then concentrated in vacuo.Chromatography of the resulting residue on silica gel, eluting withhexane:ethyl acetate (7:3) to remove nitrophenol, then eluting withethyl acetate/methanol/acetic acid (100:10:1) gave 780 mg (20%) of thetitle compound. ¹H NMR (CDCl₃, 400 MHz): 1.18 (s, 9H), 1.26 (s, 3H),2.82 (dd, 2H), 5.70 (dd, 2H), 6.53 (dd, J=8 Hz, J=2 Hz, 1H), 6.46 (d,J=8 Hz, 1H), 6.68 (d, J=2 Hz). MS (ESI) m/z 385.10 (M+H⁺).

Example 24 Methyl2-{N′-[(3-Carboxypropionyloxymethoxy)carbonyl]-hydrazino}-3-(3,4-dihydroxy-phenyl)-2-methyl-propionate(147)

[0372] Step A: [(3-Benzyloxycarbonyl)propionyloxymethyl]-4-NitrophenylCarbonate (148)

[0373] To a solution of succinic acid monobenzyl ester (1.1 g, 5.28mmol) and iodomethyl-p-nitrophenyl carbonate (1.9 g, 5.90 mmol) in 20 mLanhydrous chloroform was added silver carbonate (2.2 g, 7.97 mmol). Thereaction mixture was heated to reflux for 5 h before cooling to roomtemperature. The mixture was then filtered through a pad of celite andthe filtrate was diluted with 100 mL of ethyl acetate. The organic layerwas washed with brine (3×50 mL), dried over MgSO₄ and concentrated invacuo. The crude product was purified by radial chromatography (5% ethylacetate/hexane to 40% ethyl acetate/hexane) to afford 1.5 g (68%) of thetitle compound.

[0374] Step B: Methyl2-{N′-[((3-Benzyloxycarbonyl)propionyloxymethoxy)carbonyl]-hydrazino}-3-(3,4-dihydroxy-phenyl)-2-methyl-propionate(149)

[0375] To an ice cold solution of 107 (210 mg, 0.71 mmol) in 2 mL DMFwas dropwise added triethylamine (0.39 mL, 2.79 mmol) and 148 (300 mg,0.81 mmol) in DMF (2 mL). The resulting mixture was allowed to warm toroom temperature over 1 h and stirred for 10 h. The reaction mixture wasthen diluted with 50 mL ethyl acetate and washed with saturated ammoniumchloride (2×30 mL). The organic layer was separated, dried over MgSO₄and concentrated in vacuo. The residue was purified by radialchromatography to afford 70 mg (20%) of the title compound.

[0376] Step C: Methyl2-{N′-[(3-Carboxypropionyloxymethoxy)carbonyl]-hydrazino}-3-(3,4-dihydroxy-phenyl)-2-methyl-propionate(147)

[0377] To a flask containing 10 mg of 10% Pd—C was added a solution of149 in 2 mL ethyl acetate under nitrogen. The resulting mixture wasdegassed several times, and then hydrogen gas was introduced (viaballoon). The suspended mixture was stirred vigorously for 12 h. Thereaction mixture was then filtered through a pad of celite. Afterremoving the solvent under reduced pressure, the residue was purified byreverse phase LC/MS to afford 14 mg (25%) of the title compound. ¹H-NMR(400 MHz, CD₃OD): δ 6.63 (d, J=8.0 Hz, 1H), 6.54 (d, J=1.6 Hz, 1H), 6.43(dd, J=8.0, 1.6 Hz, 1H), 5.70 (s, 2H), 3.66 (s, 3H), 2.84 (Abq, J=26.8,13.6 Hz, 2H), 2.54-2.63 (m, 4H), 1.24 (s, 3H). MS (ESI) m/z 415.2(M+H⁺).

Example 255-[3-(3,4-Dihydroxy-phenyl)-2-hydrazino-2-methyl-propionyl]-oxy-pentanoicAcid (151)

[0378] Step A:5-[3-(3,4-Bis-benzyloxy-phenyl)-2-(N′-tert-butoxycarbonyl-hydrazino)-2-methyl-propionyl]-oxypentanoicAcid Benzyl Ester (152)

[0379] To a solution of 5-bromo-pentanoic acid benzyl ester (210 mg,0.78 mmol) in 1 mL DMF was added3-(3,4-bis-benzyloxy-phenyl)-2-(N′-tert-butoxycarbonyl-hydrazino)-2-methyl-propionicacid (329 mg, 0.65 mmol) and potassium bicarbonate (78 mg, 0.78 mmol).The resulting mixture was heated to 80° C. and stirred for 12 h. Thereaction mixture was then cooled to room temperature and diluted with 50mL of ethyl acetate. The organic layer was washed with 10% citric acidaqueous solution (2×20 mL) followed by brine (2×20 mL). The organiclayer was dried over MgSO₄ and concentrated in vacuo. The crude residuewas purified by radial chromatography (CH₂Cl₂ to 10% MeOH/CH₂Cl₂) toafford 210 mg (46%) of the title compound.

[0380] Step B:5-[2-(N′-tert-Butoxycarbonyl-hydrazino)-3-(3,4-dihydroxy-phenyl)-2-methyl-propionyl]-oxypentanoicAcid (153)

[0381] To a flask containing 40 mg of 10% Pd—C was added a solution ofthe above product in 6 mL of MeOH under nitrogen. The resulting reactionsolution was degassed several times, then hydrogen gas was introducedvia a balloon apparatus. After stirring vigorously for 12 h, thereaction mixture was filtered through a pad of celite and the filtratewas concentrated in vacuo.

[0382] Step C:5-[3-(3,4-Dihydroxy-phenyl)-2-hydrazino-2-methyl-propionyl]-oxy-pentanoicAcid (151)

[0383] The crude 153 was dissolved in 4 mL anhydrous CH₂Cl₂ and treatedwith 2 mL of trifluoroacetic acid at 0° C. The reaction mixture wasallowed to warm to room temperature and stirred for 1 h. After removingthe solvent under reduced pressure, the residue was purified by reversephase LC/MS to afford 55 mg (26% overall yield) of the title compound:¹H-NMR (400 MHz, CD₃OD): δ 6.68 (d, J=8.0 Hz, 1H), 6.55 (d, J=1.6 Hz,1H), 6.45 (dd, J=8.0, 1.6 Hz, 1H), 4.09-4.18 (m, 2H), 2.79-2.92 (Abq,J=36.8, 13.2 Hz, 2H), 2.30 (t, J=6.8 Hz, 2H), 1.59-1.68 (m, 4H), 1.42(s, 3H). MS (ESI) m/z 327.2 (M+H⁺).

Example 263-(3,4-Bis-ethoxycarbonyloxy-phenyl)-2-hydrazino-2-methyl-propionic AcidCarboxymethyl Ester (154)

[0384] Step A:3-(3,4-Bis-ethoxycarbonyloxy-phenyl)-2-(N′-tert-butoxycarbonyl-hydrazino)-2-methyl-propionicAcid Tert-butoxycarbonyl-methyl Ester (155)

[0385] To an ice cold solution of 146 (410 mg, 1 mmol) in 4 mL of CH₂Cl₂was added Et₃N (0.30 mL, 2.15 mmol) followed by ethyl chloroformate (0.2mL, 2.09 mmol). The resulting mixture was allowed to warm to roomtemperature and stirred for 12 h. The mixture was then diluted withethyl acetate (50 mL) and washed with 10% citric acid aqueous solution(2×30 mL), dried over MgSO₄, filtered and concentrated in vacuo. Thecrude product was purified by radial chromatography (CH₂Cl₂ to 10%MeOH/CH₂Cl₂) to afford 0.42 g of the title compound.

[0386] Step B:3-(3,4-Bis-ethoxycarbonyloxy-phenyl)-2-hydrazino-2-methyl-propionic AcidCarboxymethyl Ester (154)

[0387] Compound 155 was dissolved in 2 mL CH₂Cl₂ and treated with 1 mLtrifluoroacetic acid at 0° C. The resulting mixture was allowed to warmto room temperature and stirred for 1 h. The reaction mixture was cooledto 0° C. again and a solution (1 mL) of 4 N HCl in dioxane was added.After stirring at room temperature for 2 h, the solvent was removed invacuo. The crude residue was purified by reverse phase LC/MS to afford103 mg (24% overall yield) of the title compound. ¹H-NMR (400 MHz,CD₃OD): δ 7.14-7.22 (m, 3H), 4.49-4.69 (Abq, J=62.8, 14.8, 2H),4.24-4.29 (m, 4H), 3.03-3.13 (q, J=13.6 Hz), 1.33 (t, J=6.0 Hz, 6H). MS(ESI) m/z 429.2 (M+H⁺).

Example 27(S)-3-(3,4-Bis-isobutyryloxy)phenyl-2-hydrazino-2-methylpropionic acidacetoxymethyl Ester (160)

[0388] Following the procedure for preparation of compound 101, andsubstituting ethyl chloroformate with isobutyryl chloride, provided thetitle compound. ¹H NMR (D₂O, 400 MHz): δ 1.11 (d, 6H), 1.13 (d, 6H),1.39 (s, 3H), 1.99 (s, 3H), 2.70 (septet, 2H), 2.97 (dd, 2H), 5.86 (dd,2H), 6.93-7.07 (m, 3H). MS (ES) m/z 439.28 (M+H⁺).

Example 28(S)-3-(3,4-Bis-isobutyryloxy)phenyl-2-hydrazino-2-methylpropionic Acid2,2-dimethyl-propionyloxymethyl Ester (161)

[0389] Following the procedure for preparation of compound 101, andsubstituting ethyl chloroformate with isobutyryl chloride andbromomethylacetate with iodomethyl pivalate, provided the titlecompound. ¹H NMR (CD₃OD, 400 MHz): δ 1.24 (s, 9H), 1.28 (d, 6H), 1.30(d, 6H), 1.45 (s, 3H), 2.79 (septet, 2H), 2.93 (dd, 2H), 5.63 (dd, 2H),7.10-7.13 (m, 3H). MS (ESI) m/z 481.28 (M+H⁺).

Example 29(S)-3-(3,4-Bis-propionyloxy)phenyl-2-hydrazino-2-methylpropionic AcidAcetoxymethyl Ester (162)

[0390] Following the procedure for preparation of compound 101, andsubstituting ethyl chloroformate with propionyl chloride, provided thetitle compound. ¹H NMR (CD₃OD, 400 MHz): δ 1.22 (t, 6H), 1.47 (s, 3H),2.59 (q, 4H), 3.08 (dd, 2H), 5.83 (dd, 2H), 7.09-7.17 (m, 3H). MS (ESI)m/z 411.31 (M+H⁺).

Example 30(S)-3-[3,4-Bis-(2,2-dimethylpropionyloxy)phenyl]-2-hydrazino-2-methylpropionicAcid Acetoxymethyl Ester (163)

[0391] Following the procedure for preparation of compound 101, andsubstituting ethyl chloroformate with 2,2-dimethylpropionyl chloride,provided the title compound. ¹H NMR (CD₃OD, 400 MHz): δ 1.33 (s, 9H),1.34 (s, 9H), 1.46 (s, 3H), 2.12 (s, 3H), 3.08 (dd, 2H), 5.83 (dd, 2H),7.05-7.12 (m, 3H). MS (ESI) m/z 467.35 (M+H⁺).

Example 31(S)-3-[3,4-Bis-(2,2-dimethylpropionyloxy)phenyl]-2-hydrazino-2-methylpropionicAcid 2,2-dimethyl-propionyloxymethyl Ester (164)

[0392] Following the procedure for preparation of compound 101, andsubstituting ethyl chloroformate with 2,2-dimethyl-propionyl chlorideand bromomethylacetate with iodomethyl pivalate, provided the titlecompound. ¹H NMR (CD₃OD, 400 MHz): δ 1.24 (s, 9H), 1.33 (s, 9h), 1.34(s, 9H), 1.44 (s, 3H), 3.07 (dd, 2H), 5.87 (dd, 2H), 7.07-7.15 (m, 3H).MS (ESI) m/z 509.41 (M+H⁺).

Example 32(S)-3-(3,4-Bis-ethoxycarbonyloxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and (1S)-isobutyryloxy-2-methylpropyl Esters (165)

[0393] Compound 101 was treated with Boc anhydride to form compound101a. To a suspension of 101a (270 mg, 0.57 mmol) and silver carbonate(198 mg, 0.72 mmol) in dichloromethane, 1-chloro-2-methylpropylisobutyrate (172 mg, 1.5 mmol) was added and stirred at 38° C. for 16 h.After removing the solvent, the residue was partitioned between ethylacetate and 10% citric acid. The organic phase was separated, dried overMgSO₄ and concentrated. The resulting residue was treated with 30%trifluoroacetic acid in dichloromethane at room temperature for 30 min.After removing the solvent, the resulting residue was purified byreverse phase preparative HPLC to afford 19 mg of the title compounds asa mixture of two diastereoisomers. ¹H NMR (CD₃OD, 400 MHz): δ 1.05 (d,6H), 1.20 (t, 6H), 1.39 (d, 6H), 1.38 (s, 1.7H), 1.50 (s, 1.3H), 2.1 (m,1H), 2.62 (m, 1H), 3.10 (m 2H), 4.3 (q, 4H), 6.6 (dd, 0.6H), 6.70 (dd,0.4H), 7.18-7.24 (m, 3H). MS (ESI) m/z 513.32 (M+H⁺).

Example 33(S)-3-(3,4-Bis-ethoxycarbonyloxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and (1S)-acetoxy 2-methylpropyl Esters (166)

[0394] Following the procedure for preparation of compound 165, andsubstituting 1-chloro-2-methylpropyl isobutyrate with1-chloro-2-methylpropyl acetate, provided the title compounds as amixture of two diastereoisomers. ¹H NMR (CD₃OD, 400 MHz): δ 1.01 (d,6H), 1.37 (t, 6H), 1.40(s, 1.2H), 1.46 (s, 1.8H), 3.11 (dd, 2H), 4.30(q, 4H), 6.62 (dd, 0.4H), 6.68 (dd, 0.6H), 7.18-7.27 (m, 3H). MS (ESI)m/z 485.21 (M+H⁺).

Example 34(S)-3-(3,4-Bis-ethoxycarbonyloxy)phenyl-2-hydrazino-2-methylpropionicAcids 1(R)- and 1(S)-isobutyryloxyethyl Esters (167)

[0395] Following the procedure for preparation of compound 165, andsubstituting 1-chloro-2-methylpropyl isobutyrate with 1-chloroethylisobutyrate, provided the title title compounds as a mixture of twodiastereoisomers. ¹H NMR (CD₃OD, 400 MHz): δ 1.18 (d, 6H), 2.36 (t, 6H),1.41 (s, 1.3H), 1.26 (s, 1.7H), 1.34 (d, 1.3H), 1.36 (d, 1.7H), 2.60 (q,1H), 2.98-3.17 (m, 2H), 4.28 (q, 4H), 6.88 (dd, 1H), 7.16-7.28 (m, 3H).MS (ESI) m/z 485.27 (M+H⁺).

Example 35(S)-3-(3,4-Bis-ethoxycarbonyloxy)phenyl-2-hydrazino-2-methylpropionicAcid Isobutyryloxymethyl Ester (168)

[0396] Following the procedure for preparation of compound 165, andsubstituting 1-chloro-2-methylpropyl isobutyrate with chloromethylisobutyrate, provided the title compound. ¹H NMR (CD₃OD, 400 MHz): 61.20 (d, 6H), 1.35 (t, 6H), 1.44 (s, 3H), 2.65 (septet, 1H), 3.10 (dd,2H), 4.30 (q, 4H), 5.88 (dd, 2H), 7.17-7.25 (m, 3H). MS (ESI) m/z 471.25(M+H⁺).

Example 36 (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcid 2-methylbenzoyloxymethyl Ester (169)

[0397] Following the procedure for preparation of compound 104, andsubstituting bromomethyl acetate with iodomethyl 2-methylbenzoatefollowed by trifluoro acetic acid (TFA) treatment, provided the titlecompound. ¹H NMR (CD₃OD, 400 MHz): δ 1.46 (s, 3H), 2.60 (s, 3H), 2.93(dd, 2H), 6.08 (s, 2H), 6.44-6.64 (m, 3H), 7.33-7.99 (m, 4H). MS (ESI)m/z 375.26 (M+H⁺).

Example 37 (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcid 2,6-dimethylbenzoyloxymethyl Ester (170)

[0398] Following the procedure for preparation of compound 104, andsubstituting bromomethyl acetate with iodomethyl 2,6-dimethylbenzoatefollowed by TFA treatment, provided the title compound. ¹H NMR (CD₃OD,400 MHz): δ 1.40 (s, 3H), 2.06 (s, 6H), 2.93 (dd, 2H), 5.98 (dd, 2H),6.37-6.55 (m, 3H), 6.98-7.21 (m, 3H). MS (ESI) m/z 389.28 (M+H⁺).

Example 38 (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcid Ethoxycarbonyloxymethyl Ester (171)

[0399] Step A:(S)-2-(N′-tert-Butoxycarbonyl)hydrazino-3-(3,4-dihydroxy)phenyl-2-methylpropionicAcid ethoxycarbonyloxymethyl Ester (172)

[0400] A mixture of chloromethyl ethyl carbonate (0.556 g, 4 mmol) andsodium iodide (600 mg, 4 mmol) in acetone was stirred at roomtemperature for 1 h. To that mixture was added CsHCO₃ (0.776 g, 4 mmol)and compound 102 (1.33 g, 4 mmol), respectively. The resulting mixturewas stirred at room temperature for 16 h. After removing the solventunder reduced pressure, the residue was partitioned between ethylacetate and 10% citric acid. The organic phase was separated, dried overMgSO₄, and concentrated. The resulting residue was purified by silicagel chromatography, eluting with hexane: ethyl acetate (5:5) to affordthe title compound.

[0401] Step B: (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcid Ethoxycarbonyloxymethyl Ester (171)

[0402] The above compound 172 was treated with 30% trifluoroacetic acidin dichloromethane at room temperature for 30 min. After removing thesolvent, the resulting residue was purified by reverse phase preparativeHPLC to afford 190 mg of the title compound. ¹H NMR (D₂O, 400 MHz): δ1.14 (t, 3H), 1.38 (s, 3H), 2.84 (dd, 2H), 4.10 (q, 2H), 5.62 (dd, 2H),6.42-6.66 (m, 3H). MS (ESI) m/z 329.23 (M+H⁺).

Example 39(S)-3-(3,4-Bis-ethoxycarbonyloxy)phenyl-2-hydrazino-2-methylpropionicAcid Ethoxycarbonyloxymethyl Ester (173)

[0403] Following the procedure for preparation of compound 106, andsubstituting compound 108 with compound 172, provided the titlecompound. ¹H NMR (CD₃OD, 400 MHz): δ 1.30 (t, 3H), 1.34 (t, 6H), 1.44(s, 3H), 3.08 (dd, 2H), 4.28 (q, 6H), 5.85 (dd, 2H), 7.15-7.23 (m, 3H).MS (ESI) m/z 473.21 (M+H⁺).

Example 40 (S)-3-(3,4-Diacetoxy)phenyl-2-hydrazino-2-methylpropionicAcid Ethoxycarbonyloxymethyl Ester (174)

[0404] Following the procedure for preparation of compound 106, andsubstituting ethyl chloroformate with acetyl chloride and compound 108with compound 172, provided the title compound. ¹H NMR (CD₃OD, 400 MHz):δ 1.31 (t, 3H), 1.45 (s, 3H), 2.25 (s, 6H), 3.08 (dd, 2H), 4.25 (q, 2H),5.85 (dd, 2H), 7.10-7.18 (m, 3H). MS (ESI) m/z 413.17 (M+H⁺).

Example 41(S)-3-(3,4-Bis-isobutyryloxy)phenyl-2-hydrazino-2-methylpropionic AcidEthoxycarbonyloxymethyl Ester (175)

[0405] Step A:(S)-3-(3,4-Bis-isobutyryloxy)phenyl-2-(N′-tert-butoxycarbonyl)hydrazino-2-methylpropionicAcid (176)

[0406] A mixture of compound 102, TEA and isobutyric anhydride indichloromethane was stirred at room temperature for 2 h. After workingup with diluted HCl and extracted with EtOAc, the organic layer wasseparated and dried over Na₂SO₄. Removal of the solvent gave the titlecompound, which was used in the next step without further purification.

[0407] Step B:(S)-3-(3,4-Bis-isobutyryloxy)phenyl-2-hydrazino-2-methylpropionic AcidEthoxycarbonyloxymethyl Ester (175)

[0408] Following the procedure for preparation of compound 165, andsubstituting 1-chloro-2-methylpropyl isobutyrate with chloromethyl ethylcarbonate and compound 110 with compound 176, provided the titlecompound. ¹H NMR (CD₃OD, 400 MHz): δ 1.30 (d, 6H), 1.32 (t, 3H), 1.41(s, 3H), 2.80 (septet, 2H), 3.08 (dd, 2H), 4.26 (q, 2H), 5.85 (dd, 2H),7.10-7.15 (m, 3H). MS (ESI) m/z 469.26 (M+H⁺).

Example 42(S)-3-(3,4-Bis-isobutyryloxy)phenyl-2-hydrazino-2-methylpropionic Acids(1R)- and (1S)-ethoxycarbonyloxyethyl Esters (177)

[0409] Following the procedure for preparation of compound 175, andsubstituting chloromethyl ethyl carbonate with 1-chloroethyl ethylcarbonate, provided the title compounds as a mixture of twodiastereoisomers. ¹H NMR (CD₃OD, 400 MHz): δ 1.28 (d, 12H), 1.30 (s,3H), 1.45 (s, 1.3H), 1.48 (s, 1.7H), 1.52 (d, 1.3H), 1.58 (d, 1.7H),2.80 (septet, 2H), 3.08 (dd, 2H), 4.22 (q, 2H), 5.77 (dd, 0.4H), 5.80(dd, 0.6H), 7.08-7.19 (m, 3H). MS (ESI) m/z 483.38 (M+H⁺).

Example 43(S)-3-(3,4-Bis-ethoxycarbonyloxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and (1S)-ethoxycarbonyloxyethyl Esters (178)

[0410] Following the procedure for preparation of compound 175, andsubstituting 1-chloro-2-methylpropyl isobutyrate with 1-chloroethylethyl carbonate and isobutyric anhydride with ethylchloroformate,provided the title compounds as a mixture of two diastereoisomers. ¹HNMR (CD₃OD, 400 MHz): δ 1.15 (t, 3H), 1.18 (t, 6H), 1.35 (d, 3H), 1.39(s, 3H), 2.85-3.08 (m, 2H), 4.06 (q, 2H), 4.16 (q, 4H), 6.77 (dd, 0.4H),6.81 (dd, 0.6H), 7.05-7.16 (m, 3H). MS (ESI) m/z 487.34 (M+H⁺).

Example 44 (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and (1S)-ethoxycarbonyloxyethyl Esters (179)

[0411] Step A:(S)-3-(3,4-Bis-tert-butoxycarbonyloxy)phenyl-2-(N′-tert-butoxycarbonylhydrazino)-2-methylpropionicAcid (180)

[0412] Following the procedure for preparation of compound 175, andsubstituting ethylchloroformate with Boc anhydride, provided the titlecompound. ¹H NMR ((CDCl₃, 400 MHz): δ 1.34 (s, 3H), 1.44 (s, 9H), 1.56(s, 18H), 3.08 (dd, 2H), 7.11-7.18 (m, 3H). MS (ESI) m/z 527.32 (M+H⁺).

[0413] Step B: (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and (1S)-ethoxycarbonyloxyethyl Esters (179)

[0414] Following the procedure for preparation of compound 178, and theresulting mixture was treated with TFA to afford the title compounds asa mixture of two diastereoisomers. ¹H NMR (CD₃OD, 400 MHz): δ 1.13 (t,3H), 1.36 (s, 3H), 1.40 (d, 3H), 2.75-2.95 (m, 2H), 4.09 (q, 2H), 6.44.(d, 0.4H), 6.47 (d, 0.6H), 6.55-6.70 (m, 3H). MS (ESI) m/z 343.25(M+H⁺).

Example 45 (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and (1S)-isopropoxycarbonyloxyethyl Esters (181)

[0415] Following the procedure for preparation of compound 175, andsubstituting chloromethyl ethyl carbonate with 1-chloroethyl isopropylcarbonate and isobutyric anhydride with Boc anhydride, provided thetitle compounds as a mixture of two diastereoisomers. ¹H NMR (D₂O, 400MHz): δ 1.12 (d, 6H), 1.32-1.39 (m, 6H), 2.77-2.98 (m, 2H), 3.08 (dd,2H), 6.46 (m, 0.45H), 6.48 (m, 0.55H), 6.53-6.65 (m, 3H). MS (ESI) m/z357.24 (M+H⁺).

Example 46(S)-3-(3,4-Bis-isobutyryloxy)phenyl-2-hydrazino-2-methyl)propionic Acids(1R)- and (1S)-isopropoxycarbonyloxyethyl Esters (182)

[0416] Following the procedure for preparation of compound 175, andsubstituting chloromethyl ethyl carbonate with 1-chloroethyl isopropylcarbonate, provided the title compounds as a mixture of twodiastereoisomers. ¹H NMR (CD₃OD, 400 MHz): δ 1.26-1.33 (m, 18), 1.45 (s,1.3H), 1.48 (s, 1.7H), 1.53 (d, 1.3H), 1.57 (d, 1.7H), 2.80 (septet,2H), 2.98-3.16 (m, 2H), 6.75 (q, 0.4H), 6.79 (q, 0.6H), 7.08-7.18 (m,3H). MS (ESI) m/z 497.31 (M+H⁺).

Example 47 (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and (1S)-cyclohexyloxycarbonyloxyethyl Esters (183)

[0417] Step A: 1-chloroethyl Cyclohexyl Carbonate (184)

[0418] To a mixture of cyclohexanol (10.9 g, 10.9 mmol), pyridine (8.62g, 10.9 mmol) in dichloromethane was added 1-chloroethyl chloroformate(15.59, 10.9 mmol) at ° C. The resulting mixture was stirred at roomtemperature for 60 min. The mixture was partitioned between hexane and10% citric acid. The organic phase was separated and dried over MgSO₄.Removal of the solvent gave the title compound, which was used in thenext reaction without further purification.

[0419] Step B: (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and (1S)-cyclohexyloxycarbonyloxyethyl Esters (183)

[0420] Following the procedure for preparation of compound 175, andsubstituting chloromethyl ethyl carbonate with 1-chloroethyl cyclohexylcarbonate, provided the title compounds as a mixture of twodiastereoisomers. ¹H NMR (D₂O, 400 MHz): δ 1.08-1.24 (m, 3H), 1.33-1.39(m, 9H), 1.42-1.58 (m, 2H), 1.64-1.75 (m, 2H), 2.72-2.94 (m, 2H), 4.52(m, 1H), 6.43-6.70 (m, 4H). MS (ESI) m/z 397.33 (M+H⁺).

Example 48 (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and (1S)-{[(2,6-dimethylcyclohexyloxy)carbonyl]oxy}ethylEsters (185)

[0421] Following the procedure for preparation of compound 183, andsubstituting cyclohexanol with 2,6-dimethylcyclohexanol, provided thetitle compounds as a mixture of two diastereoisomers. MS (ESI) m/z425.31 (M+H⁺).

Example 49 (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and(1S)-{[(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yloxy)carbonyl]oxy}ethylEsters (186)

[0422] Following the procedure for preparation of compound 183, andsubstituting cyclohexanol with (1R)-endo-(+)-fenchyl, provided the titlecompounds as a mixture of two diastereoisomers. MS (ESI) m/z 451.31(M+H⁺).

Example 50 (S)-3-(3,4-Dihydroxy)phenyl-2-hydrazino-2-methylpropionicAcids (1R)- and (1S)-{[(adamantan-2-yloxy)carbonyl]oxy}ethyl Esters(187)

[0423] Following the procedure for preparation of compound 183, andsubstituting cyclohexanol with 2-adamantanol, provided the titlecompounds as a mixture of two diastereoisomers. MS (ESI) m/z 449.31(M+H⁺).

General Procedure for Preparation of Compounds 188-209 and 211-224 viaAlkylation of a Carbidopa Derivative with a Halide

[0424] To a mixture of compound 102 (1 mmol) and cesium hydrogencarbonate (1.2 mmol) in dimethylacetamide or acetone was added a halidecompound 17 (1.2 mmol). After stirring at appropriate temperature (roomtemperature to 60° C.) for 16 h, the mixture was filtrated and thefiltrate was concentrated under reduced pressure to give an oilyresidue. Chromatography (SiO₂, 3:97 methanol/ethyl acetate or 40:60ethyl acetate/hexane) of the residue gave Boc protected carbidopa ester(yield: 45% to 75%). The Boc protecting group was removed using 30%trifluoroacetic acid/dichloromethane for 30 min at room temperature. Theproduct was purified by HPLC (0.05% formic acid/water/acetonitrile). Insome cases, the formic acid salt was converted to an HCl salt by adding1 eq. of 0.1N HCl solution. The final product was obtained uponre-lyophilization.

Example 51 Phenylmethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (188)

[0425] The title compound (76 mg) was prepared as a white solidaccording to the general procedure. ¹H NMR (CD₃OD): δ 1.47 (s, 3H), 2.91(dd, J=13.6 Hz, 2H), 5.19 (dd, J=12.4 Hz, 2H), 6.36 (dd, J=7.6 Hz, 1H),6.58 (s, 1H), 6.62 (d, J=7.6 Hz, 1H), 7.33 (m, 5H). MS (ESI) m/z 317.2(M+H⁺).

Example 52 (4-Methylphenyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (189)

[0426] The title compound was prepared as a white solid according to thegeneral procedure. ¹H NMR (CD₃OD): δ 1.45 (s, 3H), 2.35 (s, 3H), 2.90(m, 2H), 5.14 (dd, J=12.0 Hz, 2H), 6.33 (dd, J=7.6 Hz, 1H), 6.57 (s,1H), 6.61 (d, J=7.6 Hz, 1H), 7.17 (dd, J=8.4 Hz, 4H). MS (ESI) m/z 331.2(M+H⁺).

Example 53 (3-Methoxyphenyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (190)

[0427] The title compound was prepared as a white solid according to thegeneral procedure. ¹H NMR (CD₃OD): δ 1.44 (s, 3H), 2.87 (dd, J=13.6 Hz,2H), 3.79 (s, 3H), 5.13 (dd, J=12.0 Hz, 2H), 6.36 (dd, J=7.6 Hz, 1H),6.57 (s, 1H), 6.63 (d, J=7.6 Hz, 1H), 6.90 (m, 4H), 7.26 (t, J=7.6 Hz,1H). MS (ESI) m/z 347.2 (M+H⁺).

Example 54 4-Pyridylmethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (191)

[0428] The title compound was prepared as a white solid according to thegeneral procedure. ¹H NMR (CD₃OD): δ 1.60 (s, 3H), 2.95 (dd, J=13.6 Hz,2H), 5.74 (s, 2H), 6.49 (dd, J=8 Hz, 1H), 6.51 (d, J=2 Hz, 1H), 6.63 (d,J=8 Hz, 1H), 7.75 (d, J=6.8 Hz, 2H), 8.75 (d, J=6.8 Hz, 2H). MS (ESI)m/z 318.1 (M+H⁺).

Example 55 3-Pyridylmethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (192)

[0429] The title compound was prepared as a white solid according to thegeneral procedure. ¹H NMR (CD₃OD): δ 1.60 (s, 3H), 2.95 (dd, J=13.6 Hz,2H), 5.37 (s, 2H), 6.42 (d, J=8 Hz, 1H,), 6.44 (s, 1H), 6.60 (d, J=8 Hz,1H), 8.02 (dd, J=8 Hz, 1H), 8.37 (d, J=8 Hz, 1H), 8.73 (s, 1H), 8.82 (d,J=6 Hz, 1H). MS (ESI) m/z 318.1 (M+H⁺).

Example 56 (2-Fluorophenyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (193)

[0430] The title compound was prepared as a white solid according to thegeneral procedure. ¹H NMR (CD₃OD): δ 1.46 (s, 3H), 2.90 (dd, J=13.6 Hz,2H), 5.23 (dd, J=12.4 Hz, 2H), 6.36 (d, J=7.6 Hz, 1H), 6.57 (s, 1H),6.61 (d, J=7.6 Hz, 1H), 7.14 (m, 2H), 7.38 (m, 2H). MS (ESI) m/z 335.1(M+H⁺).

Example 57 (3-Fluorophenyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (194)

[0431] The title compound was prepared as a white solid according to thegeneral procedure. ¹H NMR (CD₃OD): δ 1.48 (s, 3H), 2.92 (dd, J=13.6 Hz,2H), 5.20 (dd, J=12.4 Hz, 2H), 6.36 (d, J=7.6 Hz, 1H), 6.57 (s, 1H),6.63 (d, J=7.6 Hz, 1H), 7.10 (m, 3H), 7.38 (m, 1H); MS (ESI) m/z 335.2(M+H⁺).

Example 58 (4-Fluorophenyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (195)

[0432] The title compound was prepared as a white solid according to thegeneral procedure. ¹H NMR (CD₃OD): δ 1.47 (s, 3H), 2.90 (m, 2H), 5.16(dd, J=12.4 Hz, 2H), 6.36 (dd, J=7.6 Hz, 1H), 6.57 (s, 1H), 6.63 (d,J=7.6 Hz, 1H), 7.1 (dd, J=8.4 Hz, 2H), 7.33 (dd, J=8.8 Hz, 2H). MS (ESI)m/z 335.1 (M+H⁺).

Example 59 (4-Chlorophenyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (196)

[0433] The title compound was prepared as a white solid according to thegeneral procedure. ¹H NMR (CD₃OD): δ 1.47 (s, 3H), 2.90 (dd, J=13.6 Hz,2H), 5.16 (dd, J=12.8 Hz, 2H), 6.36 (d, J=8.4 Hz, 1H), 6.57 (s, 1H),6.63 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H).MS (ESI) m/z 351.2 (M+H⁺).

Example 60 (3-Trifluoromethylphenyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (197)

[0434] The title compound was prepared as a white solid according to thegeneral procedure. ¹H NMR (CD₃OD): δ 1.45 (s, 3H), 2.88 (dd, J=13.6 Hz,2H), 5.24 (dd, J=12.4 Hz, 2H), 6.35 (d, J=7.6 Hz, 1H), 6.56 (s, 1H),6.61 (d, J=7.6 Hz, 1H), 7.59 (m, 4H). MS (ESI) m/z 385.2 (M+H⁺).

Example 61 (4-Trifluoromethylphenyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (198)

[0435] The title compound was prepared as a white solid according to thegeneral procedure. ¹H NMR (CD₃OD): δ 1.47 (s, 3H), 2.88 (dd, J=13.6 Hz,2H), 5.23 (dd, J=12.4 Hz, 2H), 6.38 (d, J=7.6 Hz, 1H), 6.57 (s, 1H),6.63 (d, J=7.6 Hz, 1H), 7.10 (dd, J=8.4 Hz, 4H). MS (ESI) m/z 385.2(M+H⁺).

Example 62 2-Phenoxyethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (199)

[0436] The title compound was prepared as a white solid using2-bromo-1-phenoxyethane according to the general procedure. ¹H NMR(CD₃OD): δ 1.48 (s, 3H), 2.92 (dd, J=13.6 Hz, 2H), 4.20 (t, J=4.8 Hz,2H), 4.52 (m, 2H), 6.49 (d, J=8.0 Hz, 1H), 6.61 (s, 1H), 6.63 (d, J=8.0Hz, 1H), 6.91 (m, 3H), 7.13 (m, 2H). MS (ESI) m/z 347.3 (M+H⁺).

Example 63 2-(4-Methylphenoxy)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (200)

[0437] The title compound was prepared as a white solid using2-bromo-1-(4-methylphenoxy)ethane according to the general procedure. ¹HNMR (CD₃OD): δ 1.46 (s, 3H), 2.27 (s, 3H), 2.92 (dd, J=13.6 Hz, 2H),4.19 (t, J=4.8 Hz, 2H), 4.51 (m, 2H), 6.49 (d, J=8.0 Hz, 1H), 6.61 (s,1H), 6.63 (d, J=8.0 Hz, 1H), 6.82 (m, 2H), 7.08 (d, J=8.4 Hz, 2H). MS(ES) m/z 361.2 (M+H⁺).

Example 64 2-(3-Methylphenoxy)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (201)

[0438] The title compound was prepared as a white solid using2-bromo-1-(3-methylphenoxy)ethane according to the general procedure. ¹HNMR (CD₃OD): δ 1.47 (s, 3H), 2.31 (s, 3H), 2.99 (dd, J=13.6 Hz, 2H),4.21 (t, J=4.8 Hz, 2H), 4.51 (m, 2H), 6.49 (d, J=8.0 Hz, 1H), 6.61 (s,1H), 6.63 (d, J=8.0 Hz, 1H), 6.74 (m, 3H), 7.15 (t, J=7.6 Hz, 1H). MS(ESI) m/z 361.3 (M+H⁺).

Example 65 2-(4-n-Butylphenoxy)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (202)

[0439] The title compound was prepared as a white solid using2-bromo-1-(4-n-butylphenoxy)ethane according to the general procedure.¹H NMR (CD₃OD): δ 0.94 (t, J=6.8 Hz, 3H), 1.32 (m, 2H), 1.45 (s, 3H),1.57 (m, 2H), 2.55 (t, J=8.0 Hz, 2H), 2.89 (m, 2H), 4.21 (t, J=4.4 Hz,2H), 4.52 (m, 2H), 6.50 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 6.64 (d, J=8.4Hz, 1H), 6.84 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H). MS (ESI) m/z403.2 (M+H⁺).

Example 66 2-(4-Methoxyphenoxy)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (203)

[0440] The title compound was prepared as a white solid using2-bromo-1-(4-methoxyphenoxy)ethane according to the general procedure.¹H NMR (CD₃OD): δ 1.47 (s, 3H), 2.92 (dd, J=13.6 Hz, 2H), 3.74 (s, 3H),4.17 (m, J=4.8 Hz, 2H), 4.49 (m, 2H), 6.50 (d, J=8.4 Hz, 1H), 6.61 (s,1H), 6.64 (d, J=8.0 Hz, 1H), 6.86 (m, 4H). MS (ESI) m/z 377.2 (M+H⁺).

Example 67 2-(2-Fluorophenoxy)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (204)

[0441] The title compound was prepared as a white solid using2-bromo-1-(2-fluorophenoxy)ethane according to the general procedure. ¹HNMR (CD₃OD): δ 1.45 (s, 3H), 2.90 (m, 2H), 4.31 (m, 2H), 4.54 (m, 2H),6.50 (d, J=7.6 Hz, 1H), 6.60 (s, 1H), 6.64 (d, J=8.0 Hz, 1H), 6.95 (m,1H), 7.10 (m, 3H). MS (ESI) m/z 365.2 (M+H⁺).

Example 68 2-(3-Fluorophenoxy)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (205)

[0442] The title compound was prepared as a white solid using2-bromo-1-(3-fluorophenoxy)ethane according to the general procedure. ¹HNMR (CD₃OD): δ 1.46 (s, 3H), 2.90 (m, 2H), 4.24 (m, 2H), 4.52 (t, J=4.0Hz, 2H), 6.50 (d, J=8.0 Hz, 1H), 6.70 (m, 5H), 7.27 (q, J=8.0 Hz, 1H).MS (ESI) m/z 365.3 (M+H⁺).

Example 69 2-(4-Fluorophenoxy)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (206)

[0443] The title compound was prepared as a white solid using2-bromo-1-(4-fluorophenoxy)ethane according to the general procedure. ¹HNMR (CD₃OD): δ 1.46 (s, 3H), 2.12 (q, J=2.0 Hz, 2H), 2.91 (dd, J=13.6Hz, 2H), 3.96 (m, 2H), 4.36 (m, 2H), 6.45 (d, J=7.6 Hz, 1H), 6.58 (s,1H), 6.67 (d, J=7.6 Hz, 1H), 6.90 (m, 2H), 7.25 (m, 2H). MS (ESI) m/z365.2 (M+H⁺).

Example 70 2-(2-Chlorophenoxy)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (207)

[0444] The title compound was prepared as a white solid using2-bromo-1-(2-chlorophenoxy)ethane according to the general procedure. ¹HNMR (CD₃OD): δ 1.47 (s, 3H), 2.93 (dd, J=13.6 Hz, 2H), 4.31 (m, 2H),4.55 (m, 2H), 6.49 (dd, J=8.0 Hz, 1H), 6.61 (s, 1H), 6.62 (d, J=8.4 Hz,1H), 6.95 (t, J=7.2 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.27 (t, J=7.6 Hz,1H), 7.36 (d, J=8.0 Hz, 1H). MS (ESI) m/z 381.2 (M+H⁺).

Example 71 2-(4-Chlorophenoxy)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (208)

[0445] The title compound was prepared as a white solid using2-bromo-1-(4-chlorophenoxy)ethane according to the general procedure. ¹HNMR (CD₃OD): δ 1.46 (s, 3H), 2.92 (dd, J=13.6 Hz, 2H), 4.21 (t, J=4.0Hz, 2H), 4.51 (m, 2H), 6.49 (d, J=8.0 Hz, 1H), 6.61 (s, 1H), 6.64 (d,J=8.4 Hz, 1H), 6.92 (m, 2H), 7.26 (m, 2H). MS (ESI) m/z 381.2 (M+H⁺).

Example 72 (4-Chlorophenoxy)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (209)

[0446] The title compound was prepared as a white solid using4-chloro-1-(chloromethoxy)benzene according to the general procedure. ¹HNMR (CD₃OD): δ 1.38 (s, 3H), 2.82 (dd, J=13.6 Hz, 2H), 5.81 (dd, J=6 Hz,J=16 Hz, 2H), 6.40 (d, J=8.0 Hz, 1H), 6.57 (s, 1H), 6.62 (d, J=8.4 Hz,1H), 6.93 (d, J=10 Hz, 2H), 7.79 (d, J=10 Hz, 2H). MS (ESI) m/z 367.2(M+H⁺).

Example 73 (4-Chlorophenoxy)methyl(S)-3-(3,4-diethoxycarbonyloxyphenyl)-2-hydrazino-2-methylpropanoate(210)

[0447] To a mixture of Boc protected (4-chlorophenoxy)methyl(2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (639 mg,1.37 mmol) and triethylamine (0.38 mL, 2.74 mmol) in dry dichloromethanewas added diethyl pyrocarbonate (0.41 mL, 2.74 mmol) and a catalyticamount of 4-dimethylaminopyridine (DMAP), respectively, at 0° C. Afterstirring at 0° C. to room temperature for 2 h. the reaction was quenchedwith 10% citric acid, and the mixture was extracted withdichloromethane. The organic phase was separated and dried over sodiumsulfate. After removing the solvent under reduced pressure,chromatography (SiO2, 20% ethyl acetate/hexane) of the residue gave 650mg (78%) of Boc protected(2S)-3-(3,4-diethoxycarbonyloxyphenyl)-2-hydrazino-2-methylpropanoate,which was treated with 30%TFA/DCM at room temperature for 30 min toremove Boc. After removing the solvent, the residue was purified by HPLC(0.05% trifluoroacetic acid/water/acetonitrile) to give 100 mg of thetitle compound as a white powder. ¹H NMR (CD₃OD): δ 1.32 (s, 3H), 1.27(t, J=7.2 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H), 2.95 (dd, J=13.6 Hz, 2H),4.34 (q, J=7.2 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 5.84 (dd, J=6 Hz, J=14Hz, 2H), 7.07 (d, J=8.0 Hz, 1H), 7.15 (s, 1H), 7.24 (d, J=8.4 Hz, 1H),7.10 (d, J=8 Hz, 2H), 7.38 (d, J=8 Hz, 2H). MS (ESI) m/z 513.1 (M+H⁺).

Example 74 (Phenoxycarbonyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (211)

[0448] The title compound was prepared as a white solid using phenyl2-bromoacetate according to the general procedure. ¹H NMR (CD₃OD): δ1.46 (s, 3H), 2.92 (dd, J=13.6 Hz, 2H), 5.07 (s, 2H), 6.56 (dd, J=8.0Hz, J=2 Hz, 1H), 6.71 (d, J=2 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 7.15 (d,J=8 Hz, 2H), 7.26 (t, J=8 Hz, 1H), 7.40 (t, J=8 Hz, 2H). MS (ESI) m/z361.2 (M+H⁺).

Example 75 [(2′-Methylphenyl)oxycarbonyl]methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (212)

[0449] The title compound was prepared as a white solid using2′-methylphenyl 2-bromoacetate according to the general procedure. ¹HNMR (CD₃OD): δ 1.50 (s, 3H), 2.20 (s, 3H), 2.92 (dd, J=13.6 Hz, 2H),5.12 (s, 2H), 6.55 (dd, J=8.0 Hz, J=2 Hz, 1H), 6.66 (d, J=2 Hz, 1H),6.68 (d, J=8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 7.20 (m, 2H), 7.27 (d, J=8Hz, 1H). MS (ESI) m/z 375.2 (M+H⁺).

Example 76 [(2,6-Dimethylphenyl)oxycarbonyl]methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (213)

[0450] The title compound was prepared as a white solid using2′,6′-dimethylphenyl 2-bromoacetate according to the general procedure.¹H NMR (CD₃OD): δ 1.50 (s, 3H), 2.17 (s, 6H), 3.00 (dd, J=13.6 Hz, 2H),5.17 (s, 2H), 6.56 (dd, J=8.0 Hz, J=2 Hz, 1H), 6.66 (d, J=2 Hz, 1H),6.68 (d, J=8 Hz, 1H), 7.07 (m, 3H). MS (ESI) m/z 389.2 (M+H⁺).

Example 77 [Benzyloxycarbonyl]methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (214)

[0451] The title compound was prepared as a white solid usingphenylmethyl 2-bromoacetate according to the general procedure. ¹H NMR(DMSO-d₆): δ 1.18 (s, 3H), 2.74 (dd, J=13.6 Hz, 2H), 4.81 (s, 2H), 5.17(s, 2H), 6.39 (dd, J=8.0 Hz, J=2 Hz, 1H), 6.52 (d, J=2 Hz, 1H), 6.57 (d,J=8 Hz, 1H), 7.36 (m, 5H). MS (ESI) m/z 375.2 (M+H⁺).

Example 78 2-Oxo-2-phenylethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (215)

[0452] The title compound was prepared as a white solid using2-bromo-1-phenylethan-1-one according to the general procedure. ¹H NMR(CD₃OD): δ 1.52 (s, 3H), 3.04 (dd, J=13.6 Hz, 2H), 5.65 (dd, J=12 Hz,2H), 6.57 (dd, J=8.0 Hz, J=2 Hz, 1H), 6.67 (d, J=2 Hz, 1H), 6.71 (d, J=8Hz, 1H), 7.71 (t, J=8.8 Hz, 2H), 7.69 (t, J=8.8 Hz, 1H), 8.01 (D, J=8.8Hz, 2H). MS (ESI) m/z 345.2 (M+H⁺).

Example 79 (Methoxycarbonyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (216)

[0453] The title compound was prepared as a white solid using methyl2-bromoacetate according to the general procedure. ¹H NMR (CD₃OD): δ1.48 (s, 3H), 2.98 (dd, J=13.6 Hz, 2H), 3.80 (s, 3H), 4.82 (s, 2H), 6.53(dd, J=8.0 Hz, J=2 Hz, 1H), 6.63 (d, J=2 Hz, 1H), 6.69 (d, J=8 Hz, 1H).MS (ESI) m/z 299.1 (M+H⁺).

Example 80 (t-Butoxycarbonyl)methyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (217)

[0454] The title compound was prepared as a white solid using t-butyl2-bromoacetate according to the general procedure. ¹H NMR (CD₃OD): δ1.47 (s, 3H), 1.51 (s, 9H), 2.98 (dd, J=13.6 Hz, 2H), 4.70 (s, 2H), 6.53(dd, J=8.0 Hz, J=2 Hz, 1H), 6.62 (d, J=2 Hz, 1H), 6.69 (d, J=8 Hz, 1H).MS (ESI) m/z 341.2 (M+H⁺).

Example 81 (1S)-(Methoxycarbonyl)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (218)

[0455] The title compound was prepared as a white solid using methyl(2S)-2-bromopropanoate according to the general procedure. ¹H NMR(CD₃OD): δ 1.38 (s, 3H), 1.50 (d, J=7.2 Hz, 3H), 2.88 (m, J=13.6 Hz,2H), 3.80 (s, 3H), 5.26 (q, J=7.2 Hz, 1H), 6.50 (dd, J=8.0 Hz, J=2 Hz,1H), 6.60 (d, J=2 Hz, 1H), 6.68 (d, J=8 Hz, 1H). MS (ESI) m/z 313.2(M+H⁺).

Example 82 (1R)-(Methoxycarbonyl)ethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (219)

[0456] The title compound was prepared as a white solid using methyl(2R)-2-bromopropanoate according to the general procedure. ¹H NMR(CD₃OD): δ 1.43 (s, 3H), 1.49 (d, J=7.2 Hz, 3H), 2.89 (dd, J=13.6 Hz,2H), 3.76 (s, 3H), 5.26 (q, J=7.2 Hz, 1H), 6.49 (dd, J=8.0 Hz, J=2 Hz,1H), 6.59 (d, J=2 Hz, 1H), 6.68 (d, J=8 Hz, 1H). MS (ESI) m/z 313.3(M+H⁺).

Example 83 2-Acetyloxyethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (220)

[0457] The title compound was prepared as a white solid using2-bromoethyl acetate according to the general procedure. MS (ESI) m/z313.2 (M+H⁺).

Example 84 2-Phenylethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (221)

[0458] The title compound was prepared as a white solid using(2-bromoethyl)benzene according to the general procedure. ¹H NMR(CD₃OD): δ 1.39 (s, 3H), 2.84 (dd, J=13.6 Hz, 2H), 2.95 (t, J=7.2 Hz,2H), 4.36 (m, 2H), 6.31 (d, J=7.6 Hz, 1H), 6.53 (s, 1H), 6.65 (d, J=8.4Hz, 1H), 7.20 (m, 3H), 7.29 (m, 2H). MS (ESI) m/z 331.2 (M+H⁺).

Example 85 3-Phenylpropyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (222)

[0459] The title compound was prepared as a white solid using(3-bromopropyl)benzene according to the general procedure. ¹H NMR(CD₃OD): δ 1.46 (s, 3H), 1.97 (q, J=7.6 Hz, 2H), 2.65 (t, J=6.0 Hz, 2H),2.90 (dd, J=13.6 Hz, 2H), 4.17 (m, 2H), 6.45 (d, J=8.4 Hz, 1H), 6.58 (s,1H), 6.68 (d, J=8.0 Hz, 1H), 7.17 (m, 3H), 7.26 (m, 2H). MS (ESI) m/z345.2 (M+H⁺).

Example 86 3-Phenoxypropyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (223)

[0460] The title compound was prepared as a white solid using3-bromo-1-phenoxypropane according to the general procedure. ¹H NMR(CD₃OD): δ 1.46 (s, 3H), 2.12 (q, J=2.0 Hz, 2H), 2.91 (dd, J=13.6 Hz,2H), 3.96 (m, 2H), 4.36 (m, 2H), 6.45 (d, J=7.6 Hz, 1H), 6.58 (s, 1H),6.67 (d, J=7.6 Hz, 1H), 6.90 (m, 3H), 7.25 (m, 2H). MS (ESI) m/z 361.2(M+H⁺).

Example 87 2-Morpholin-4-ylethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (224)

[0461] The title compound was prepared as a white solid using4-(2-bromoethyl)morpholine according to the general procedure. ¹H NMR(CD₃OD): δ 1.53 (s, 3H), 2.91 (dd, J=13.6 Hz, 2H), 3.08 (m, 4H), 3.43(m, 2H), 3.92 (m, 4H), 4.42 (m, 2H,), 6.50 (d, J=7.6 Hz, 1H), 6.59 (s,1H), 6.72 (d, J=7.6 Hz, 1H). MS (ESI) m/z 340.2 (M+H⁺).

Example 88 Cyclohexyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (226)

[0462] Acetyl chloride (1 mL) was slowly added to cyclohexanol (5 mL) at0° C. After stirring at 0° C. for 10 min, carbidopa (294 mg, 1.5 mmol)was added slowly as solid. The resulting mixture was warmed to 50° C.for 16 h. After cooling to room temperature, ethyl acetate (40 mL) wasadded and product was extracted with water (4×5 mL), then the aqueousphase was lyophilized to give the crude product. HPLC of the crudeproduct afforded 50 mg of the title compound as an oil. ¹H NMR (CD₃OD):δ 1.46 (s, 3H), 1.52-1.80 (m, 10H), 2.92 (dd, J=13.6 Hz, 2H,), 4.85 (m,1H), 6.49 (d, J=7.6 Hz, 1H), 6.59 (s, 1H), 6.68 (d, J=7.6 Hz, 1H). MS(ESI) m/z 309.3 (M+H⁺).

Example 89 Phenyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (227)

[0463] A mixture of Boc-carbidopa (296 mg, 1 mmol) andN,N′-carbonyldiimimidazole (356 mg, 2.2 mmol) in anhydroustetrahydrofuran (THF) (20 mL) was stirred at room temperature for 6 h.Then, to the mixture was added phenol (1.2 mmol) followed by addition ofa catalytic amount of 4-dimethylaminopyridine (DMAP). The resultingmixture was stirred at 50° C. for 16 h. After concentration, the residuewas dissolved in ethyl acetate, and washed with cold 5% aqueous NaHCO₃and then 10% citric acid. The organic phase was separated and dried overNa₂SO₄ After filtration, the solvent was removed under reduced pressure.The resulting residue was purified by chromatography (SiO2, 50:50 ethylacetate/hexane) to provide Boc-protected carbidopa ester (yield: 20% to25%). The Boc group was removed with 30% trifluoroaceticacid/dichloromethane at room temperature for 30 min. Afterconcentration, HPLC (0.05% trifluoroacetic acid/water/acetonitrile)followed by lyophilization afforded 90 mg of the title compound. ¹H NMR(CD₃OD): δ 1.61 (s, 3H), 3.04 (dd, J=13.6 Hz, 2H), 6.59 (d, J=8.0 Hz,1H), 6.70 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 7.09 (d, J=8 Hz), 7.26 (t,J=8 Hz), 7.40 (t, J=8 Hz). MS (ESI) m/z 303.2 (M+H⁺).

Example 90 4-Methylthiophenyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate (228)

[0464] The title compound was prepared as a solid following theprocedure outlined in Example 98 but substituting 4-methylthiophenol forphenol. ¹H NMR (CD₃OD): δ 1.43 (s, 3H), 2.49 (s, 3H) 3.13 (dd, J=13.6Hz, 2H), 6.58 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 6.73 (d, J=8.4 Hz, 1H),7.03 (d, J=8 Hz), 7.30 (d, J=8 Hz). MS (ESI) m/z 349.1 (M+H⁺).

Example 91 (S)-3-(3,4-Dihydroxyphenyl)-2-hydrazino-2-methylpropionicAcid Carboxymethylester (229)

[0465] Step A: tert-Butyl(S)-α-[3-(3,4-dihydroxyphenyl)-2-(N′-tert-butoxycarbonyl-hydrazino)-2-methylpropionyloxy]-acetate(230)

[0466] To a stirred solution of 102 (650 mg, 2 mmol) in anhydrousN,N-dimethylformamide (7 mL) in a 50 mL capacity screwcap-septum vialwas added cesium hydrogencarbonate (480 mg, 2.5 mmol). After havingstirred at room temperature for 30 min, a solution of tert-butylα-bromoacetate (2.5 mmol) was introduced into the reaction mixture. Theresulting mixture was stirred at room temperature for 3 h and then, at45° C. overnight (˜12 h). The reaction mixture was cooled to roomtemperature and filtered. The residue was washed with ethyl acetate (25mL×4). The combined filtrates were washed with water (25 mL×2), driedover anhydrous sodium sulfate and concentrated. The residue waschromatographed over silica gel using a gradient of 10-100% ethylacetate and hexane to afford 710 mg (81%) of the title compound as alight yellow thick liquid. MS (ESI) m/z 463.16 (M+Na⁺) and 439.02(M−H⁻).

[0467] Step B: (S)-3-(3,4-Dihydroxyphenyl)-2-hydrazino-2-methylpropionicAcid Carboxymethylester (229)

[0468] A solution of compound 230 (441 mg, 1 mmol) in 1:1 (v/v)dichloromethane and trifluoroacetic acid was stirred at room temperaturefor 8 h (monitored by LC/MS). After removing the solvent under reducedpressure at room temperature, the residue was purified by preparativeLC/MS technique to afford 165 mg (58%) of the title compound as a lightyellow solid. ¹H NMR (400 MHz, CD₃OD): δ1.39 (3H, s), 2.93 (2H, m), 4.56(1H, d), 4.75 (1H, d), 6.50 (1H, dd), 6.60 (1H, d), 6.67 (1H, d). MS(ESI) m/z 285.26 (M+H⁺) and 283.13 (M−H⁻).

Example 92(S)-4-[3-(3,4-Dihydroxyphenyl)-2-hydrazino-2-methylpropionyloxy]-butyricAcid (231)

[0469] Following the procedure described for preparation of compound229, and substituting tert-butyl bromomethyl acetate with2,4-dimethoxybenzyl γ-bromobutyrate, provided the title compound (41%over 2 steps) as a colorless thick liquid. ¹H NMR (400 MHz, CD₃OD):δ1.45 (3H, s), 1.95 (2H, q), 2.35 (2H, t), 2.86(2H, m), 4.21 (2H, m),6.46 (1H, dd), 6.56(1H, d), 6.68 (1H, d). MS (ESI) m/z 313.21 (M+H⁺) and311.18 (M−H⁻).

Example 93(S)-6-[3-(3,4-Dihydroxyphenyl)-2-hydrazino-2-methylpropionyl]-oxy-hexanoicAcid (232)

[0470] Following the procedure described for preparation of compound229, and substituting tert-butyl bromomethyl acetate with4-methoxybenzyl 6-bromohexanoate, provided the title compound (20% over2 steps) as a colorless thick liquid. ¹H NMR (400 MHz, DMSO-d₆): δ1.28(3H, s), 1.50 (4H, m), 1.99 (2H, broad s), 2.17 (2H, t), 4.03 (2H, m),6.33 (1H, dd), 6.47(1H, d), 6.60 (1H, d). MS (ESI) m/z 341.26 (M+H⁺) and339.21 (M−H⁻).

Example 94(S)-3-[3-(3,4-Dihydroxyphenyl)-2-hydrazino-2-methylpropionyloxy]methylbenzoicAcid (233)

[0471] Following the procedure described for preparation of compound229, and substituting tert-butyl bromomethyl acetate with2,4-dimethoxybenzyl m-chloromethyl-benzoate, provided the title compound(26% over 2 steps) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ1.42 (3H,s), 2.79 (1H, d), 2.90 (1H, d), 5.2 (2H, m), 6.35 (1H, dd), 6.56 (1H,d); 6.60 (1H, d), 7.45 (2H, m), 7.97 (2H, m). MS (ESI) m/z 361.15 (M+H⁺)and 359.17 (M−H⁻).

Example 95 (S)-3-(3,4-Dihydroxyphenyl)-2-hydrazino-2-methylpropionicAcid 4-carboxymethyl-benzyl Ester (234)

[0472] Following the procedure described for preparation of compound229, and substituting tert-butyl bromomethyl acetate with2,4-dimethoxybenzyl p-bromomethyl-benzoate, provided the title compound(25% over 2 steps) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ1.40 (3H,s), 2.85 (2H, m), 3.30 (2H, m), 3.58 (2H, d), 5.11 (1H, d), 6.31 (1H,m), 6.58 (2H, m), 7.27 (4H, m). MS (ESI) m/z 375.17 (M+H⁺) and 373.13(M−H⁻).

Example 96 1(R)- and 1(S)-Methyl-2-Phenylethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropionates (237)

[0473] Following the procedure described for preparation of compound229, and substituting tert-butyl bromomethyl acetate with2-phenylisopropyl bromide, provided the colorless thick liquid titlecompound as a mixture of two diastereoisomers. ¹HNMR (CD₃OD): δ1.24-1.22 (3H, m), 1.31 (3H, s), 2.87-2.60 (4H, m), 5.14-5.05 (1H, m),6.37-6.12 (1H, m), 6.53-6.46 (1H, m), 6.63-6.55 (1H, m), 7.27-7.14 (5H,m). MS (ESI) m/z 345.26 (M+H⁺).

Example 97 Cinnamyl(S)-3-(3,4-Dihydroxyphenyl)-2-hydrazino-2-methylpropionate (238)

[0474] Step A: N-Fmoc Carbidopa (239)

[0475] To a stirred solution of carbidopa (5.0 g, 22.12 mmol) in drymethanol was added 9-fluorenylmethyloxycarbonyl chloride (Fmoc-chloride)(6.3 g, 24.3 mmol) and triethylamine (3.5 mL, 25 mmol) at 0° C. Theresulting mixture was stirred at room temperature overnight. Thereaction mixture was diluted with water (200 mL) and extracted withethyl acetate (2×200 mL). The combined extracts were washed with brine(100 mL), dried over magnesium sulfate and evaporated to give 10 g ofcrude title compound as a light brown liquid, which was used in the nextstep without further purification. MS (ESI) m/z 449.26 (M+H⁺).

[0476] Step B: Cinnamyl(S)-3-(3,4-Dihydroxyphenyl)-2-hydrazino-2-methylpropionate (238)

[0477] To a stirred suspension of compound 239 (0.9 g, 2.0 mmol) andcesium hydrogen carbonate (0.39 g, 2 mmol) in anhydrousN,N-dimethylformamide (15 mL) was added cinnamyl bromide (0.12 mL, 1.1mmol) and then, the reaction mixture was stirred at room temperatureovernight (monitored by LC/MS). The reaction mixture was cooled to roomtemperature and filtered. The residue was washed with ethyl acetate (25mL×4). The combined filtrates were washed with water (25 mL×2), driedover magnesium sulfate and evaporated the solvent. The residue waspurified by flash chromatography using 1:1 (v/v) ethyl acetate/hexane aseluent to afford the crude cinnamyl ester derivative of N-Fmoc carbidopaas a yellow thick liquid, which was then dissolved in drytetrahydrofuran (10 mL). To this solution was added a catalytic amountof DBU (0.2 mL) followed by 1-octanethiol (2 mL). The resulting mixturewas stirred at room temperature for 15 min (monitored by LC/MS). Uponcompletion of the reaction, the reaction mixture was washed with diethylether (2×0 mL) and the residue was purified by preparative LC/MStechnique. The title compound (15%) was isolated as a colorless thickliquid. ¹HNMR (CD₃OD): δ 1.39 (3H, s), 2.80 (2H, m), 4.74 (2H, dd), 6.27(1H, m), 6.43 (1H, m), 6.67-6.56 (3H, m), 7.42-7.21 (5H, m). MS (ESI)m/z 343.04 (M+M⁺).

Example 98 1(R)- and 1(S)-Phenylethyl(S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropionates (240)

[0478] Following the procedure described for preparation of compound228, and substituting cinnamyl bromide with 1-bromo-1-phenylethane,provided the colorless thick liquid title compound (10%) as a mixture oftwo diastereoisomers. ₁HNMR (CD₃OD): δ 1.36 (3H, broad s), 1.51 (3H,broad s), 2.69-2.88 (2H, m), 5.81-5.89 (1H, m), 6.39 (1H, m), 6.49-6.57(1H, m), 6.60 (1H, m), 7.34-7.26 (5H, m). MS (ESI) m/z 331.25 (M+H⁺).

Example 99 2-Methylbenzoic Acid(S)-4-(2-hydrazino-2-methoxycarbonyl-propyl)-2-hydroxy-phenyl Ester(241) and 2-Methylbenzoic Acid(S)-5-(2-hydrazino-2-methoxycarbonyl-propyl)-2-hydroxy-phenyl Ester(242)

[0479] Following the procedure for preparation of compounds 125 and 126,and substituting 2,6-dimethyl-benzoyl chloride with 2-methyl-benzoylchloride and carbidopa with carbidopa methyl ester, provided the titlecompounds 241 and 242 as a mixture of two inseparable regioisomers. ¹HNMR (CD₃OD): δ1.42 (s, 1.5H), 1.46 (s, 1.5H), 2.60 (bs, 3H), 2.90-3.05(m, 2H), 3.76 (s, 1.5H), 3.80 (s, 1.5H), 6.66 (dd, 1H), 6.76 (d, 1H),7.04 (d, 1H), 7.32 (m, 2H), 7.50 (m, 1H), 8.12 (d, 1H).

Example 100 4-Pyridylmethyl(S)-3-(3,4-diethylcarbonyloxyphenyl)-2-hydrazino-2-methylpropanoate(243)

[0480] Following the procedure for preparation of compounds 210 inExample 73, and substituting N-Boc protected (4-chlorophenoxy)methyl(2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate with N-Bocprotected 4-pyridylmethyl(2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoate, providedthe title compound. ₁H NMR (CD₃OD): δ1.34 (t, J=7.2 Hz, 3H), 1.35 (t,J=7.2 Hz, 3H), 1.61 (s, 3H), 3.13 (q, J=7.2 Hz, 2H), 4.30 (q, J=7.2 Hz,2H), 5.43 (s, 2H), 7.18 (d, J=2 Hz, 17.21 (d, J=2 Hz, 1H), 7.72 (d, J=6Hz, 1H), 8.75 (d, J=6 Hz, 1H), 8.73 (s, 1H), 8.82 (d, J=6 Hz, 1H). MS(ESI) m/z 462.17 (M+H+).

Example 101 Uptake of L-Dopa Following Administration of L-Dopa andCarbidopa-Dopa Prodrugs in Rats

[0481] Sustained release oral dosage forms, which release drug slowlyover periods of 6-24 hours, generally release a significant proportionof the dose within the colon. Thus drugs suitable for use in such dosageforms can exhibit good colonic absorption. This experiment was conductedto assess the uptake and resultant blood levels of L-dopa,coadministered (intracolonically or intraperitoneally) with a carbidopaprodrug, for assessing suitability for use in an oral sustained releasedosage form. Bioavailability of L-dopa was calculated relative to oralcoadministration of L-dopa and carbidopa. Relative bioavailability ofL-dopa is F_(rel) in Table 1 and is expressed as a percent of the L-dopabioavailability of orally administered L-dopa, coadministered withcarbidopa.

[0482] Step A: Administration Protocol

[0483] Rats were obtained commercially and were pre-cannulated in theboth the ascending colon and the jugular vein. Animals were conscious atthe time of the experiment. All animals were fasted overnight and until4 hours post-dosing of L-Dopa. Carbidopa or carbidopa prodrug wasadministered as a solution in water or citrate buffer either orally, orintraperitoneally or intracolonically at a dose equivalent to 25 mg ofcarbidopa per kg. Either at the same time or 1 hour after carbidopadosing, L-dopa HCl salt was administered as a solution (in water)directly into the colon via the cannula at a dose equivalent to 75 mg ofL-Dopa per kg. Blood samples (0.3 mL) were obtained from the jugularcannula at intervals over 8 hours and were quenched immediately byaddition of sodium metabisulfite to prevent oxidation of L-Dopa. Bloodwas then further quenched with methanol/perchloric acid to preventhydrolysis of the prodrug. Blood samples were analyzed as describedbelow.

[0484] Step B: Sample Preparation for Colonic Absorbed Drug

[0485] 1. In blank 1.5 mL tubes, 300 μL of methanol/perchloric acid wasadded.

[0486] 2. Rat blood 300 μL was collected at different time points intoEDTA tubes containing 75 μL of sodium metabisulfite, and vortexed tomix. A fixed volume of blood (100 μL) was immediately added into theeppendorf tube and vortexed to mix.

[0487] 3. Ten microliters of an L-dopa standard stock solution (0.04,0.2, 1, 5, 25, 100 μg/mL) and 10 μL of the 10% sodium metabisulfate wasadded to 80 μL of blank rat blood to make up a final calibrationstandard (0.004, 0.02, 0.1, 0.5, 2.5, 10 μg/mL). Then 300 μL of 50/50methanol/perchloric acid was added into each tube followed by 20 μL ofp-chlorophenylalanine.

[0488] 4. Samples were vortexed and centrifuged at 14,000 rpm for 10min.

[0489] 5. Supernatant was analyzed by LC/MS/MS.

[0490] Step C: LC/MS/MS Analysis

[0491] An API 40000 LC/MS/MS spectrometer equipped with Agilent 1100binary pumps and a CTC HTS-PAL autosampler were used in the analysis. AZorbax XDB C8 4.6×150 mm column was used during the analysis. The mobilephase was 0.1% formic acid (A) and acetonitrile with 0.1% formic acid(B). The gradient condition was: 5% B for 0.5 min, then to 98% B in 3min, then maintained at 98% B for 2.5 min. The mobile phase was returnedto 2% B for 2 min. A TurboIonSpray source was used on the API4000. Theanalysis was done in positive ion mode and the MRM transition for eachanalyte was optimized using standard solution. 5 μL of the samples wereinjected. Non-compartmental analysis was performed using WinNonlin(v.3.1 Professional Version, Pharsight Corporation, Mountain View,Calif.) on individual animal profiles. Summary statistics on majorparameter estimates was performed for C_(max) (peak observedconcentration following dosing), T_(max) (time to maximum concentrationis the time at which the peak concentration was observed), AUC_((0−t))(area under the serum concentration-time curve from time zero to lastcollection time, estimated using the log-linear trapezoidal method),AUC_((0−∞)), (area under the serum concentration time curve from timezero to infinity, estimated using the log-linear trapezoidal method tothe last collection time with extrapolation to infinity), and t_(1/2,z)(terminal half-life). Maximum concentrations of L-dopa in the blood(Cmax values) and the area under blood concentration versus time curve(AUC) values after intracolonic dosing of L-dopa with carbidopa prodrugswere significantly higher (>2-fold) than those produced from colonicadministration of L-dopa with carbidopa.

[0492] As shown in Table 1, intracolonic coadministration of L-dopa andcarbidopa results in very low relative bioavailability of L-dopa (i.e.,only 2.4% of orally coadministered L-dopa and carbidopa). By comparison,coadministration of all of the carbidopa prodrugs tabulated in Table 2with L-dopa (except the mixture of compounds 125 and 126) exhibitedimproved relative bioavailability of L-dopa. Carbidopa prodrug compounds109, 160 and 177 all exhibited at least 10-fold higher relativebioavailability of L-dopa, and compounds 101, 105, 162, 163, 167, 168,173, 175, 177, and 208 all exhibited at least 5-fold higher relativebioavailability of L-dopa. These data demonstrate that certain compoundscan be formulated as compositions suitable for effective sustained oralrelease and uptake from the colon. TABLE 1 L-Dopa Bioavailabilities inRats Average L-Dopa Relative Dose Bioavailability Carbidopa Prodrug(mg-eq Carbidopa Prodrug of L-Dopa Compound #/ L-Dopa L-dopa/ Route andDose Number F_(rel) Example # Compound kg) Vehicle (mg-eq carbidopa/kg)of Rats (%) N/A (comparative) L-Dopa 75 Water Carbidopa HCl Salt 6 2.4HCl Salt Intracolonic (25) N/A (comparative) L-Dopa 75 Water CarbidopaHCl Salt 6 100 HCl Salt Oral bolus (25)

[0493] TABLE 2 Carbidopa Prodrug Administration Schedule L-Dopa Dose(mg-eq Carbidopa Prodrug Carbidopa Prodrug L-Dopa L-dopa/ Route and DoseNumber Compound # Compound kg) Vehicle (mg-eq carbidopa/kg) of RatsCompounds 241 L-Dopa 75 Citrate Intracolonic (25) 3 and 242 (50:50Buffer mix) Compounds 125 L-Dopa 75 Citrate Intracolonic (25) 3 and 126(50:50 Buffer mix) Compounds 127 L-Dopa 75 Citrate Intracolonic (25) 3and 128 (50:50 Buffer mix) Compound 110 L-Dopa 75 Water Intracolonic(25) 3 HCl Salt Compound 109 L-Dopa 75 Water Intracolonic (50) 3 HClSalt Compound 105 L-Dopa 75 Water Intracolonic (25) 3 TFA Salt Compound101 L-Dopa 75 Water Intracolonic (25) 6 HCl Salt Compound 163 L-Dopa 75Water Intracolonic (25) 8 HCl Salt Compound 161 L-Dopa 75 WaterIntracolonic (25) 6 HCl Salt Compound 160 L-Dopa 75 Water Intracolonic(25) 6 HCl Salt Compound 162 L-Dopa 75 Water Intracolonic (25) 5 HClSalt Compound 177 L-Dopa 75 Water Intracolonic (25) 7 HCl Salt Compound168 L-Dopa 75 Water Intracolonic (25) 6 HCl Salt Compound 167 L-Dopa 75Water Intracolonic (25) 5 HCl Salt Compound 175 L-Dopa 75 WaterIntracolonic (25) 5 HCl Salt Compound 173 L-Dopa 75 Water Intracolonic(25) 5 HCl Salt Compound 174 L-Dopa 75 Water Intracolonic (25) 7 HClSalt Compound 227 L-Dopa 75 Water Intracolonic (25) 6 HCl Salt Compound164 L-Dopa 75 Water Intracolonic (25) 7 HCl Salt Compound 243 L-Dopa 75Water Intracolonic (25) 6 HCl Salt Compound 208 L-Dopa 75 WaterIntracolonic (25) 6 HCl Salt Compound 183 L-Dopa 75 Water IntracolonicHCl 5 HCl Salt Salt (25)

What is claimed is:
 1. A compound of Formula (I):

a stereoisomer thereof, an enantiomer thereof, a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing, wherein: X is selected from —OR¹⁰ and moieties of Formulae(II) and (III):

where: r is an integer from 1 to 6; Q is O or —NR¹⁵ ; R¹ is selectedfrom hydrogen and a moiety comprising Formula (IX):

R⁴ and R⁵ are independently selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, —C(O)OR²⁷,—C(O)R²⁷, —(CR¹⁶R¹⁷)OC(O)R¹¹ and moieties of Formulae (XVII) and(XVIII):

wherein o is 1-3, and the cycloheteroalkyl rings in (XVII) and (XVIII)are optionally substituted with one or more groups selected from halo,CN, NO₂, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy; or R⁴ and R⁵ together form astructure selected from Formulae (XII) to (XVI):

wherein the aryl ring in Formula (XV) is optionally substituted with oneor more groups selected from halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and—CO₂R³¹; R¹⁰ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R¹¹ isselected from hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl, or optionally, R¹¹ and either R¹⁶ or R ¹⁷, togetherwith the atoms to which R 11, and either R¹⁶ or R¹⁷ are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring, optionally towhich is fused an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring; R¹⁵ is selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, and substitutedarylalkyl; R¹⁶ and R¹⁷ are independently selected from hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,substituted carbomoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl or optionally, R¹⁶ andR¹⁷ together with the carbon atom to which R¹⁶ and R ¹⁷ are attachedform a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring; each R²⁰ and R²¹ is independentlyselected from hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, acyl, substituted acyl, alkylamino, substituted alkylamino,alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substitutedalkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl,substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, aryloxy, substituted aryloxy, carbamoyl,substituted carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino,substituted dialkylamino, halo, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy,heteroaryloxy, and substituted heteroaryloxy, or optionally, when r is1, then R²⁰ and R²¹ together with the carbon atom to which R²⁰ and R²¹are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkylor substituted cycloheteroalkyl ring, or optionally when R²⁰ and R¹⁵ arepresent and are attached to adjacent atoms then R¹⁵ and R²⁰ togetherwith the atoms to which R¹⁵ and R²⁰ are attached form a cycloheteroalkylor substituted cycloheteroalkyl ring; R²⁷ is selected from alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl; R²⁸ and R²⁹ areindependently selected from hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroalkyl, andsubstituted heteroalkyl; and R³¹ is selected from hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl; with the provisos thatwhen X is —OR¹⁰, R¹ is hydrogen, and R⁴ and R⁵ are independentlyselected from hydrogen and C₁₋₉ alkyl, C₁₋₉ aryl or C₁₋₉ arylalkyl, thenR¹⁰ is not hydrogen or C₁₋₆ alkyl; and none of R¹, R⁴, R⁵, R¹⁰, R¹¹,R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹, R²⁷, R²⁸, R²⁹, and R³¹ comprise a bile acidmoiety.
 2. A compound of Formula (Ia):

a stereoisomer thereof, an enantiomer thereof, a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing, wherein: R¹ is selected from hydrogen and the structure ofFormula (IX):

R⁴ and R⁵ are independently selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, —C(O)OR²⁷,—C(O)R²⁷, —(CR¹⁶R¹⁷)OC(O)R¹¹ and moieties of Formulae (XVII) and(XVIII):

wherein o is 1-3, and the cycloheteroalkyl rings in (XVII) and (XVIII)are optionally substituted with one or more groups selected from halo,CN, NO₂, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy; or R⁴ and R⁵ together form astructure selected from Formulae (XII) to (XVI):

wherein the aryl ring in Formula (XV) is optionally substituted with oneor more groups selected from halo, CN, OH, C,₁₋₆ alkyl, C₁₋₆ alkoxy, and—CO₂R³¹; R¹⁰ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R¹¹ isselected from hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl, or optionally, R¹¹ and either R¹⁶ or R¹⁷, together withthe atoms to which R¹¹, and either R¹⁶ or R¹⁷ are attached, form a firstcycloheteroalkyl or substituted cycloheteroalkyl ring, to which an aryl,substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring is optionally fused to said first cycloheteroalkyl or substitutedcycloheteroalkyl ring; R¹⁶ and R¹⁷ are independently selected fromhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl, andsubstituted heteroarylalkyl or optionally, R¹⁶ and R¹⁷ together with thecarbon atoms to which R¹⁶ and R¹⁷ are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring; R²⁷ is selected from hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl; R²⁸ and R²⁹ are independently selected fromhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroalkyl, and substitutedheteroalkyl; and R³¹ is selected from hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl; with the provisos that when R¹ hydrogen,and R⁴ and R⁵ are independently selected from hydrogen, C₁₋₁₉ alkyl,C₁₋₁₉ aryl or C₁₋₁₉ arylalkyl, then R¹⁰ is not hydrogen or C₁₋₆ alkyl;and none of R¹, R⁴, R⁵, R¹⁰, R¹¹, R¹⁵, R¹⁶, R¹⁷, R²⁷, R²⁸, R²⁹ , and R³¹comprise a bile acid moiety.
 3. A compound according to claim 2, whereinR⁴ and R⁵ are independently selected from moieties of Formula (XVII) and(XVIII).
 4. A compound according to claim 2, wherein R¹ is hydrogen. 5.A compound according to claim 2, wherein R¹ is a moiety comprisingFormula (IX).
 6. A compound according to claim 2, wherein R⁴ and R⁵ areindependently selected from hydrogen, alkanyl, substituted alkanyl,arylalkanyl, substituted arylalkanyl, heteroarylalkanyl, substitutedheteroarylalkanyl, cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl, and substituted cycloheteroalkanyl.
 7. A compoundaccording to claim 2, wherein R⁴ and R⁵ are independently selected fromhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl andpyridyl, where the aryl rings of the benzyl and pyridyl groups areoptionally substituted with one or more substituents selected from halo,CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.
 8. A compoundaccording to claim 2, wherein R⁴ and R⁵ are independently selected fromhydrogen, —C(O)OR²⁷, and —C(O)R²⁷.
 9. A compound according to claim 8,wherein R²⁷ is selected from C ₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈aryl, substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀arylalkyl.
 10. A compound according to claim 2, wherein R⁴ and R⁵ areindependently —C(O)OR²⁷ or —C(O)R²⁷.
 11. A compound according to claim10, wherein R²⁷ is selected from C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl,C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀arylalkyl.
 12. A compound according to claim 2, wherein R²⁷ is selectedfrom alkanyl, substituted alkanyl, cycloalkanyl, substitutedcycloalkanyl, arylalkanyl, substituted arylalkanyl, heteroarylalkanyl,and substituted heteroarylalkanyl.
 13. A compound according to claim 2,wherein R²⁷ is selected from methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and benzyl where the aryl ring of the benzyl group isoptionally substituted with one or more substituents selected from halo,CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.
 14. A compoundaccording to claim 2, wherein R²⁷ is selected from aryl, substitutedaryl, heteroaryl, and substituted heteroaryl.
 15. A compound accordingto claim 2, wherein R²⁷ is selected from phenyl, pyridyl, furyl, andthienyl, the aromatic rings of which are optionally substituted with oneor more substituents selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆alkoxy, and —CO₂R³¹.
 16. A compound according to claim 2, wherein R²⁷ isselected from C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl,substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀ arylalkyl.17. A compound according to claim 2, wherein R⁴ and R⁵ are independentlyselected from hydrogen and —(CR¹⁶R¹⁷)OC(O)R¹¹.
 18. A compound accordingto claim 17, wherein R¹¹ is selected from hydrogen, C₁₋₁₀ alkyl,substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₁₋₁₅ alkoxy,and substituted C₁₋₁₅ alkoxy.
 19. A compound according to claim 17,wherein R¹⁶ and R¹⁷ are independently selected from hydrogen, C₁₋₁₆alkyl, substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.
 20. A compound according toclaim 2, wherein R⁴ and R⁵ are both —(CR¹⁶R¹⁷)OC(O)R ¹¹.
 21. A compoundaccording to claim 20, wherein R¹¹ is selected from hydrogen, C₁₋₁₀alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₁₋₁₅alkoxy, and substituted C₁₋₁₅ alkoxy.
 22. A compound according to claim20, wherein R¹⁶ and R¹⁷ are independently selected from hydrogen, C₁₋₁₆alkyl, substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.
 23. A compound according toclaim 2, wherein R⁴ and R⁵ together with the atoms to which R⁴ and R⁵are attached are incorporated into a benzo-fused heterocyclic ring ofFormula (XIV).
 24. A compound according to claim 2, wherein R¹⁰ isselected from hydrogen, alkanyl, substituted alkanyl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl, substituted cycloheteroalkanyl, heteroarylalkanyl,and substituted heteroarylalkanyl.
 25. A compound according to claim 2,wherein R¹⁰ is selected from hydrogen, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenoxyethyl, carboxymethyl, carboxyethyl,carboxypropyl, carboxybutyl, and benzyl, and wherein said moieties areoptionally substituted with one or more substituents selected from halo,CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.
 26. A compoundaccording to claim 2, wherein R¹⁰ is selected from hydrogen, aryl,substituted aryl, heteroaryl, and substituted heteroaryl.
 27. A compoundaccording to claim 2, wherein R¹⁰ is selected from phenyl andsubstituted phenyl, and where said moieties are optionally substitutedwith one or more substituents are selected from halo, CN, NO₂, OH, C₁₋₆alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.
 28. A compound according to claim 2,wherein R¹⁰ is selected from C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈aryl, substituted C₅₋₈ aryl, —R³²OC(O)R³⁷, and —R³²OC(O)OR³⁷, where R³²is selected from C₁₋₁₀ alkylene, substituted C₁₋₁₀ alkylene, C₅₋₈arylene, substituted C₅₋₈ arylene, C₆₋₁₀ arylalkylene, and substitutedC₆₋₁₀ arylalkylene, and R³⁷ is selected from C₁₋₁₀ alkyl, substitutedC₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, andsubstituted C₆₋₁₀ arylalkyl.
 29. A compound according to claim 2,wherein R¹¹ is selected from hydrogen, alkanyl, substituted alkanyl,alkenyl, substituted alkenyl, arylalkanyl, substituted arylalkanyl,arylalkenyl, substituted arylalkenyl, cycloalkanyl, substitutedcycloalkanyl, heteroarylalkanyl, and substituted heteroarylalkanyl. 30.A compound according to claim 2, wherein R¹¹ is selected from methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and styryl, where thearyl ring of the styryl group is optionally substituted with one or moresubstituents selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,and —CO₂R³¹.
 31. A compound according to claim 2, wherein R¹¹ isselected from aryl substituted aryl, heteroaryl, and substitutedheteroaryl.
 32. A compound according to claim 2, wherein R¹¹ is selectedfrom phenyl, pyridyl, indolyl, furyl, imidazolyl, and oxazolyl, thearomatic rings of which are optionally substituted with one or moresubstituents selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,and —CO₂R³¹.
 33. A compound according to claim 2, wherein R¹¹ isselected from hydrogen, C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl,substituted C₅₋₈ aryl, C₁₋₁₅ alkoxy, and substituted C₁₋₁₅ alkoxy.
 34. Acompound according to claim 2, wherein R¹¹ is selected from methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, hexyloxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy,cyclohexyloxy, 2,6-dimethylcyclohexyloxy, fenchyloxy, and adamantyloxy.35. A compound according to claim 2, wherein R¹¹ and either R¹⁶ or R¹⁷,together with the atoms to which R¹¹, and either R¹⁶ or R¹⁷ areattached, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring, to which an aryl, substituted aryl,heteroaryl or substituted heteroaryl ring is optionally fused to saidcycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring.
 36. A compound according to claim 2, wherein R¹⁶and R¹⁷ are independently selected from hydrogen, alkanyl, substitutedalkanyl, cycloalkanyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, arylalkanyl, and substituted arylalkanyl.
 37. A compoundaccording to claim 2, wherein R¹⁶ and R¹⁷ are independently selectedfrom hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, and benzyl, where the aryl ring of thephenyl and the benzyl groups is optionally substituted with one or moresubstituents selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,and —CO₂R³¹.
 38. A compound according to claim 2, wherein R¹⁶ and R¹⁷together with the carbon atom to which R¹⁶ and R¹⁷ are attached form acycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl orsubstituted cycloheteroalkanyl ring.
 39. A compound according to claim2, wherein R¹⁶ and R¹⁷ together with the carbon atom to which R¹⁶ andR¹⁷ are attached form a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl ring.
 40. A compound according to claim 2, wherein R¹⁶ andR¹⁷ are independently selected from hydrogen, C₁₋₁₆ alkyl, substitutedC₁₋₁₆ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, andsubstituted C₆₋₁₀ arylalkyl.
 41. A compound according to claim 2,wherein R²⁸ and R²⁹ are independently selected from hydrogen, alkanyl,aryl, and alkoxycarbonyl.
 42. A compound according to claim 2, whereinR²⁸ and R²⁹ are independently selected from hydrogen, methyl, ethyl,propyl, butyl, phenyl, methoxycarbonyl, and ethoxycarbonyl.
 43. Acompound according to claim 2, wherein R²⁸ and R²⁹ are both hydrogen.44. A compound according to claim 2, wherein R³¹ is selected fromhydrogen, C₁₋₈ alkyl, and cycloalkyl.
 45. A compound according to claim2, wherein R³¹ is selected from hydrogen, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.
 46. A compound according toclaim 2, wherein R¹ is hydrogen, and R¹⁰ is selected from C₇₋₁₀ alkyl,substituted C₇₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, —R³²OC(O)R³⁷,and —R³²OC(O)OR³⁷, where R³² is selected from C₁₋₁₀ alkylene,substituted C₁₋₁₀ alkylene, C₅₋₈ arylene, substituted C₅₋₈ arylene,C₆₋₁₀ arylalkylene, and substituted C₆₋₁₀ arylalkylene, and R³⁷ isselected from C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl,substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀ arylalkyl.47. A compound according to claim 2, wherein R¹ is a moiety of Formula(IX), and R¹⁰ is selected from hydrogen, C₁₋₁₀ alkyl, substituted C₁₋₁₀alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, —R³²OC(O)R³⁷, and—R³²OC(O)OR³⁷, where R³² is selected from C₁₋₁₀ alkylene, substitutedC₁₋₁₀ alkylene, C₅₋₈ arylene, substituted C₅₋₈ arylene, C₆₋₁₀arylalkylene, and substituted C₆₋₁₀ arylalkylene, and R³⁷ is selectedfrom C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀ arylalkyl.
 48. A compoundof Formulae (Ib) or (Ic):

a stereoisomer thereof, an enantiomer thereof, a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing, wherein: Q is O or —NR¹⁵; r is an integer from 1 to 6; R¹ isselected from hydrogen, and a moiety comprising Formula (IX):

R⁴ and R⁵ are independently selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, —C(O)OR ²⁷,—C(O)R²⁷, —(CR¹⁶R¹⁷)OC(O)R¹¹ and moieties of Formulae (XVII) and(XVIII):

wherein o is 1-3, and the cycloheteroalkyl rings in (XVII) and (XVIII)are optionally substituted with one or more groups selected from halo,CN, NO₂, OH, C₁₋₆ alkyl, and C₁₋₆ alkoxy; or R⁴ and R⁵ together form astructure selected from Formulae (XII) to (XVI):

wherein the aryl ring in Formula (XV) is optionally substituted with oneor more groups selected from halo, CN, OH, C ₁₋₆ alkyl, C₁₋₆ alkoxy, and—CO₂R³¹; R¹⁰ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R¹¹ isselected from hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl, or optionally, R¹¹ and either R¹⁶ or R¹⁷ , togetherwith the atoms to which R¹¹, R¹⁶ and R¹⁷ are attached, form acycloheteroalkyl or substituted cycloheteroalkyl ring, to which an aryl,substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring is optionally fused to said cycloheteroalkyl or substitutedcycloheteroalkyl ring; R¹⁵ is selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; R¹⁶and R¹⁷ are independently selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroarylalkyl, and substituted heteroarylalkyl oroptionally, R¹⁶ and R¹⁷ together with the carbon atoms to which R¹⁶ andR¹⁷ are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring; each R²⁰ and R²¹is independently selected from hydrogen, alkyl, substituted alkyl,alkoxy, substituted alkoxy, acyl, substituted acyl, alkylamino,substituted alkylamino, alklysulfinyl, substituted alkylsulfinyl,alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substitutedalkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy,carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino,substituted dialkylamino, halo, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy,heteroaryloxy, and substituted heteroaryloxy, or optionally, when r is1, then R²⁰ and R²¹ together with the carbon atom to which R²⁰ and R²¹are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkylor substituted cycloheteroalkyl ring, or optionally when R²⁰ and R¹⁵ arepresent and are attached to adjacent atoms then R¹⁵ and R²⁰ togetherwith the atoms to which R¹⁵ and R²⁰ are attached form a cycloheteroalkylor substituted cycloheteroalkyl ring; R²⁷ is selected from hydrogen,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl; R²⁸ and R²⁹ areindependently selected from hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, cycloalkyl, substituted cycloalkyl, heteroalkyl, andsubstituted heteroalkyl; and R³¹ is selected from hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl; with the proviso thatnone of R¹, R⁴, R⁵, R¹⁰, R¹¹, R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹, R²⁷, R²⁸, R²⁹,and R³¹ comprise a bile acid moiety.
 49. A compound according to claim48, wherein R⁴ and R⁵ are independently selected moieties from Formulae(XVII), and (XVIII).
 50. A compound according to claim 48 having Formula(Ic), wherein Q is O.
 51. A compound according to claim 48 havingFormula (Ic), wherein Q comprises —NR¹⁵.
 52. A compound according toclaim 48 having Formulae (Ib) or (Ic), wherein R¹ is hydrogen.
 53. Acompound according to claim 48 having Formulae (Ib) or (Ic), wherein R¹is a moiety comprising Formula (IX).
 54. A compound according to claim48 having Formulae (Ib) or (Ic), wherein R⁴ and R⁵ are independentlyselected from hydrogen, alkanyl, substituted alkanyl, arylalkanyl,substituted arylalkanyl, heteroarylalkanyl, substitutedheteroarylalkanyl, cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl, and substituted cycloheteroalkanyl.
 55. A compoundaccording to claim 48 having Formulae (Ib) or (Ic), wherein R⁴ and R⁵are independently selected from hydrogen, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl,cyclohexyl, benzyl, and pyridyl, where the aryl rings of the benzyl andpyridyl groups are optionally substituted with one or more substituentsselected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy and —CO₂R³¹.56. A compound according to claim 48 having Formulae (Ib) or (Ic),wherein R⁴ and R⁵ are independently selected from hydrogen, —C(O)OR²⁷,and —C(O)R²⁷.
 57. A compound according to claim 56, wherein R²⁷ isselected from C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, C₅₋₈substituted aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀ arylalkyl. 58.A compound according to claim 48 having Formulae (Ib) or (Ic), whereinR⁴ and R⁵ are both independently —C(O)OR²⁷ or —C(O)R²⁷.
 59. A compoundaccording to claim 58, wherein R²⁷ is selected from C₁₋₁₀ alkyl,substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, C₅₋₈ substituted aryl, C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.
 60. A compound according toclaim 48 having Formulae (Ib) or (Ic), wherein R²⁷ is selected fromalkanyl, substituted alkanyl, cycloalkanyl, substituted cycloalkanyl,arylalkanyl, substituted arylalkanyl, heteroarylalkanyl, and substitutedheteroarylalkanyl.
 61. A compound according to claim 48 having Formulae(Ib) or (Ic), wherein R²⁷ is selected from methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and benzyl, where the aryl ring ofthe benzyl group is optionally substituted with one or more substituentsselected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.62. A compound according to claim 48 having Formulae (Ib) or (Ic),wherein R²⁷ is selected from aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl.
 63. A compound according to claim 48 havingFormulae (lb) or (Ic), wherein R²⁷ is selected from phenyl, pyridyl,furyl, and thienyl, the aromatic rings of which are optionallysubstituted with one or more substituents selected from halo, CN, NO₂,OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.
 64. A compound according toclaim 48 having Formulae (Ib) or (Ic), wherein R⁴ and R⁵ areindependently selected from hydrogen and —(CR¹⁶R ¹⁷)OC(O)R¹¹.
 65. Acompound according to claim 64, wherein R¹¹ is selected from hydrogen,C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl,C₁₋₁₅ alkoxy, and substituted C₁₋₁₅ alkoxy.
 66. A compound according toclaim 64, wherein R¹⁶ and R¹⁷ are independently selected from hydrogen,C₁₋₁₆ alkyl, substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl,C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀ arylalkyl.
 67. A compoundaccording to claim 48 having Formulae (Ib) or (Ic), wherein R⁴ and R⁵are both independently —(CR¹⁶R¹⁷)OC(O)R¹¹.
 68. A compound according toclaim 67, wherein R¹¹ is selected from hydrogen, C₁₋₁₀ alkyl,substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₁₋₁₅ alkoxy,and substituted C₁₋₁₅ alkoxy.
 69. A compound according to claim 67,wherein R¹⁶ and R¹⁷ are independently selected from hydrogen, C₁₋₁₆alkyl, substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.
 70. A compound according toclaim 48 having Formula (Ic), wherein R¹⁰ is selected from hydrogen,alkanyl, substituted alkanyl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl,heteroarylalkanyl and substituted heteroarylalkanyl, aryl, substitutedaryl, heteroaryl, and substituted heteroaryl.
 71. A compound accordingto claim 48 having Formula (Ic), wherein R¹⁰ is selected from hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopentyl, cyclohexyl, and benzyl, where the aryl ring ofthe benzyl group is optionally substituted with one or more substituentsselected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.72. A compound according to claim 48 having Formula (Ic), wherein R¹⁰ isselected from hydrogen, methyl, and ethyl.
 73. A compound according toclaim 48 having Formula (Ic), wherein R¹⁰ is selected from hydrogen,C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, and substituted C₅₋₈aryl.
 74. A compound according to claim 48 having Formula (Ib), whereinR¹¹ is selected from alkanyl, substituted alkanyl, alkenyl, substitutedalkenyl, arylalkanyl, substituted arylalkanyl, arylalkenyl, substitutedarylalkenyl, cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl,substituted cycloheteroalkanyl, heteroarylalkanyl, and substitutedheteroarylalkanyl.
 75. A compound according to claim 48 having Formula(Ib), wherein R¹¹ is selected from methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and styryl, where the aryl ring ofthe styryl group is optionally substituted with one or more substituentsare selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C ₁₋₆ alkoxy, and—CO₂R³¹.
 76. A compound according to claim 48 having Formula (Ib),wherein R¹¹ is selected from aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl.
 77. A compound according to claim 48 havingFormula (Ib), wherein R¹¹ is selected from phenyl, pyridyl, indolyl,furyl, imidazolyl, and oxazolyl, the aromatic rings of which areoptionally substituted with one or more substituents selected from halo,CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —CO₂R³¹.
 78. A compoundaccording to claim 48 having Formula (Ib), wherein R¹¹ is selected fromhydrogen, C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, substitutedC₅₋₈ aryl, C₁₋₁₅ alkoxy, and substituted C₁₋₁₅ alkoxy.
 79. A compoundaccording to claim 48 having Formula (Ib), wherein R¹¹ is selected frommethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclobutoxy,cyclopentyloxy, cyclohexyloxy, 2,6-dimethylcyclohexyloxy, fenchyloxy,and adamantyloxy.
 80. A compound according to claim 48 having Formula(Ib), wherein R¹¹ and either R¹⁶ or R¹⁷, together with the atoms towhich R¹¹ and either R¹⁶ or R¹⁷ are attached, form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring, to which an aryl, substituted aryl, heteroaryl or substitutedheteroaryl ring is optionally fused to said cycloheteroalkyl orsubstituted cycloheteroalkyl ring.
 81. A compound according to claim 2,wherein R¹ is hydrogen, R⁴ and R⁵ are each C(O)R²⁷ , R¹⁰ is selectedfrom C₁₋₄ alkyl, and R²⁷ is selected from C₁₋₄ alkyl.
 82. A compoundaccording to claim 81, wherein R²⁷ is tert-butyl.
 83. A compoundaccording to claim 81, wherein R¹⁰ is methyl or ethyl.
 84. A compoundaccording to claim 48 having Formula (Ib), wherein R¹ is hydrogen, R⁴and R⁵ are each C(O)OR²⁷, R¹⁶ is hydrogen, R²⁷ is ethyl, R¹¹ is selectedfrom C₁₋₄ alkyl, C₁₋₄ alkoxy, cyclohexyloxy, 2,6-dimethylcyclohexyloxy,fenchyloxy, and adamantyloxy, and R¹⁷ is selected from hydrogen, andC₁₋₄ alkyl.
 85. A compound according to claim 84, wherein R¹⁷ ishydrogen.
 86. A compound according to claim 84, wherein R¹⁷ is methyl.87. A compound according to claim 48 having Formula (Ib), wherein R¹ ishydrogen, R⁴ and R⁵ are each C(O)R²⁷ , R ¹⁶ is hydrogen, R²⁷ isisopropyl, R¹¹ is selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, cyclohexyloxy,2,6-dimethylcyclohexyloxy, fenchyloxy, and adamantyloxy, and R¹⁷ isselected from hydrogen, and C₁₋₄ alkyl.
 88. A compound according toclaim 87, wherein R¹⁷ is hydrogen.
 89. A compound according to claim 87,wherein R¹⁷ is methyl.
 90. A compound according to claim 48 havingFormula (Ib), wherein R¹ is hydrogen, R⁴ and R⁵ are each C(O)R²⁷, R¹⁶ ishydrogen, R²⁷ is tert-butyl, R¹¹ is selected from C₁₋₄ alkyl, C₁₋₄alkoxy, cyclohexyloxy, 2,6-dimethylcyclohexyloxy, fenchyloxy, andadamantyloxy, and R¹⁷ is selected from hydrogen, and C₁₋₄ alkyl.
 91. Acompound according to claim 90, wherein R¹⁷ is hydrogen.
 92. A compoundaccording to claim 90, wherein R¹⁷ is methyl.
 93. A compound accordingto claim 51 having Formula (Ic), wherein R¹⁵ is hydrogen.
 94. A compoundaccording to claim 51 having Formula (Ic), wherein R¹⁵ is selected frommethyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec-butyl.
 95. Acompound according to claim 51 having Formula (Ic), wherein R¹⁵ ismethyl.
 96. A compound according to claim 48 having Formulae (Ib) or(Ic), wherein R¹⁶ and R¹⁷ are independently selected from hydrogen,alkanyl, substituted alkanyl, cycloalkanyl, substituted cycloalkanyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkanyl,and substituted arylalkanyl.
 97. A compound according to claim 48 havingFormulae (Ib) or (Ic), wherein R¹⁶ and R¹⁷ are independently selectedfrom hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, and benzyl.
 98. A compound according to claim 48 having Formulae(Ib) or (Ic), wherein R¹⁶ is hydrogen and R¹⁷ is selected from hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and benzyl.
 99. A compound according to claim 48 having Formulae (Ib) or(Ic), wherein R¹⁶ and R¹⁷ together with the carbon atoms to which R¹⁶and R¹⁷ are attached form a cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl or substituted cycloheteroalkanyl ring.
 100. Acompound according to claim 48 having Formulae (Ib) or (Ic), wherein R¹⁶and R¹⁷ together with the carbon atoms to which R¹⁶ and R¹⁷ are attachedform a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
 101. Acompound according to claim 48 having Formulae (Ib) or (Ic), wherein R¹⁶and R¹⁷ are independently selected from hydrogen, C₁₋₁₆ alkyl,substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.
 102. A compound according toclaim 48 having Formula (Ic), wherein each R²⁰ and R²¹ is independentlyselected from hydrogen, alkanyl, substituted alkanyl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl, substituted cycloheteroalkanyl, halo, heteroalkanyl,substituted heteroalkanyl, heteroarylalkanyl, and substitutedheteroarylalkanyl.
 103. A compound according to claim 48 having Formula(Ic), wherein each R²⁰ and R²¹ is independently selected from hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andbenzyl.
 104. A compound according to claim 48 having Formula (Ic),wherein each R²⁰ and R²¹ is independently selected from hydrogen,alkanyl, substituted alkanyl, arylalkanyl, substituted arylalkanyl,alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, aryloxy,substituted aryloxy, dialkylamino, substituted dialkylamino,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy, andsubstituted heteroaryloxy.
 105. A compound according to claim 48 havingFormula (Ic), wherein each R²⁰ and R²¹ is independently selected fromhydrogen, alkoxy, alkylamino, aryloxy, dialkylamino, and heteroalkyloxy.106. A compound according to claim 48 having Formula (Ic), wherein eachR²⁰ and R²¹ is independently selected from hydrogen, alkanyl,substituted alkanyl, arylalkanyl, substituted arylalkanyl, acyl,substituted acyl, alkoxycarbonyl, carbamoyl, and substituted carbamoyl.107. A compound according to claim 48 having Formula (Ic), wherein eachR²⁰ and R²¹ is independently selected from hydrogen, acyl, substitutedacyl, alkoxycarbonyl, carbamoyl, and substituted carbamoyl.
 108. Acompound according to claim 48 having Formula (Ic), wherein each R²⁰ andR²¹ is independently selected from hydrogen, alkanyl, substitutedalkanyl, arylalkanyl, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl.
 109. A compound according to claim 48 havingFormula (Ic), wherein each R²⁰ and R²¹ is independently selected fromhydrogen and phenyl, optionally substituted with one or moresubstituents selected from halo, CN, NO₂, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,and —CO₂R³¹.
 110. A compound according to claim 48 having Formula (Ic),wherein r is 1 and R²⁰ and R²¹ together with the carbon atoms to whichR²⁰ and R²¹ are attached form a cycloalkanyl, substituted cycloalkanyl,cycloheteroalkanyl or substituted cycloheteroalkanyl ring.
 111. Acompound according to claim 48 having Formula (Ic), wherein r is 1 andR²⁰ and R²¹ together with the carbon atoms to which R²⁰ and R²¹ areattached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.112. A compound according to claim 48 having Formula (Ic), wherein eachR²⁰ and R²¹ is independently selected from hydrogen, C₁₋₁₆ alkyl,substituted C₁₋₁₆ alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀arylalkyl, and substituted C₆₋₁₀ arylalkyl.
 113. A compound according toclaim 48 having Formula (Ib) or (Ic), wherein R²⁸ and R²⁹ areindependently selected from hydrogen, alkanyl, aryl, and alkoxycarbonyl.114. A compound according to claim 48 having Formula (Ib) or (Ic),wherein R²⁸ and R²⁹ are independently selected from hydrogen, methyl,ethyl, propyl, butyl, phenyl, methoxycarbonyl, and ethoxycarbonyl. 115.A compound according to claim 48, having Formula (Ib) or (Ic), whereinR²⁸ and R²⁹ are both hydrogen.
 116. A compound according to claim 48having Formulae (Ib) or (Ic), wherein R³¹ is selected from hydrogen andC₁₋₈ alkyl.
 117. A compound according to claim 48 having Formulae (Ib)or (Ic), wherein R³¹ is selected from hydrogen, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.
 118. A pharmaceuticalcomposition comprising at least one pharmaceutically acceptableexcipient, and a therapeutically effective amount of at least onecompound according to any one of claims 1, 2 or
 48. 119. Thepharmaceutical composition of claim 118, wherein the pharmaceuticalcomposition further comprises at least one additional active agent. 120.The pharmaceutical composition of claim 119, wherein the at least oneadditional active agent is susceptible to decarboxylation, and theamount of the at least one compound is in an effective amount to inhibitdecarboxylation of the at least one additional active agent.
 121. Thepharmaceutical composition of claim 119, wherein the at least oneadditional active agent is selected from levodopa and prodrugs oflevodopa.
 122. The pharmaceutical composition of claim 118, wherein thepharmaceutical composition is formulated for oral administration. 123.The pharmaceutical composition of claim 122, wherein the pharmaceuticalcomposition is a sustained release formulation.
 124. The pharmaceuticalcomposition of claim 119, wherein the compound and the additional activeagent comprise a single unit dosage form.
 125. The pharmaceuticalcomposition of claim 118, wherein the at least one compound is presentin an amount effective for the treatment in a patient of a diseaseselected from Parkinson's disease, and hypertension.
 126. A method oftreating a disease in a patient, in need of such treatment, comprisingadministering to the patient a therapeutically effective amount of anactive agent that is susceptible to decarboxylation, and at least onecompound according to any of claims 1, 2 or
 48. 127. The method of claim126, wherein the disease is Parkinson's disease.
 128. The method ofclaim 126, wherein, the disease is treated by a compound susceptible todecarboxylation.
 129. The method of claim 126, wherein the active agentis selected from levodopa and prodrugs of levodopa.
 130. A method oftreating a disease in a patient in need of such treatment comprisingadministering to the patient a therapeutically effective amount of atleast one compound according to any of claims 1, 2 or
 48. 131. Themethod of claim 130, wherein the disease is hypertension.
 132. A methodof providing a therapeutically effective concentration of at least oneactive agent in the plasma of a patient, which active agent issusceptible to premature inactivation by decarboxylation, comprisingco-administering to the patient the at least one active agent and the atleast one compound according to any one of claims 1, 2 or
 48. 133. Themethod of claim 132, wherein the active agent is selected from levodopaand prodrugs of levodopa.
 134. A method of inhibiting decarboxylation ofat least one active agent in a patient, comprising administering to thepatient at least one compound according to any one of claims 1, 2 or 48.135. The method of claim 134, wherein inhibiting decarboxylationcomprises inhibiting a decarboxylase enzyme.
 136. A carbidopa prodrug,analog or derivative thereof which, when co-administered with levodopain the colon of a patient is taken up at a rate to achieve abioavailability of levodopa at least 2-fold greater than thebioavailability of levodopa without coadministration of the carbidopaprodrug, analog, or derivative thereof.